Startled?! Try Glycine!

Getting startled is natural and important, but when it happens too easily or with too exaggerated a response, this could indicate a problem. Here's how to solve it.

The ability to become startled is an adaptive behavior that protects us from being injured by a sudden threat, and prepares us for the fight-or-flight response when necessary.

Nevertheless, getting startled too easily can be a sign that something is wrong.

The Neurobiology of the Startle Reflex

The neurobiology of the startle reflex is complex. The reflex involves visual, auditory, and tactile inputs. Research has been almost exclusively on the acoustic startle reflex, and has been mostly done in animals. Much less has been done on the tactile inputs and the least has been done on the visual inputs.

Enhanced startle reflex is part of the diagnostic criteria for post-traumatic stress disorder. This reflects the role of fear in conditioning the startle response. Fear conditions it, anxiety enhances it, and pleasure inhibits it.

Most anti-anxiety drugs that inhibit it do so by lowering anxiety, and not by inhibiting the reflex itself. In other words, they modify how the brain rates the threat of the stimulus, and not on how the body reacts.

Loud noise, bright light, and female sex hormones enhance the reflex. A non-startling sensation that occurs less than a second before the startling sensation can damper it. Serotonin and acetylcholine play roles in this. Being repeatedly exposed to a startling stimulus dampens its effects.

The sensory inputs to the startle response are integrated in the brainstem, and the motor response — the actual reaction of the body — is coordinated in the spinal cord. Glutamate is the neurotransmitter that activates it. GABA inhibits it in the brainstem, and glycine inhibits it in the spinal cord.

That is, GABA inhibits the coordination of the sensory perception, and glycine inhibits the coordination of the motor response.

The Overwhelming Importance of Glycine

Hyperekplexia is a rare genetic disease causing dramatically increased startle reflex in newborns, where otherwise trivial sound and touch stimuli elicit a massive increase in muscle tension that can restrict breathing and lead to joint dislocations. An analysis of over 200 DNA samples found the most common mutation was in one of the subunits of the glycine receptor. A smaller number of mutations are in proteins downstream from glycine signaling, and some are in glycine transporters.

One of them is in a protein gephyrin, which also plays roles in assembling the response to GABA and in assembling the molybdenum cofactor needed to get rid of sulfite. Since sulfite enhances glutamate activity, this role could be important in preventing excessive activation of the startle reflex by glutamate. Thus, gephyrin deficiency could be triply aggravating the startle reflex by enhancing glutamate activity, and by impairing the activity of both GABA and glycine.

Nevertheless, it is absolutely remarkable that all of the gene mutations known to cause hyperekplexia are involved in glycine neurotransmission and none are involved exclusively in sulfite metabolism or in neurotransmission by glutamate and GABA.

Now, it may well be that too much sulfite and glutamate or too little GABA enhances the startle reflex, but can never do so to such an extent that the muscular response is so exaggerated as to be diagnosed as an independent disease.

Despite this, clonazepam is the treatment of choice for disorders of glycine neurotransmission, which predominantly increases GABA receptor activity. Strangely, the 2022 edition of the Saudubray textbook states that benzoate and ketamine have been tried but have not been effective, but states nothing about attempting high-dose glycine.

There are no randomized controlled trials testing the effect of nutritional strategies to modulate any of these neurotransmitters on the startle reflex.

So, if you find yourself with an exaggerated startle reflex, it seems to me that glycine should be the first thing to try.

Causes of Low Glycine Status

Here are reasons you could run low in glycine:

• Glycine is synthesized primarily from glucose, so decreasing carb intake can lower glycine status.

• NAD+ is needed to convert 3-phosphoglycerate from the glycolytic pathway to 3-phosphooxypyruvate, a precursor of glycine, so niacin deficiency or a respiratory chain disorder could lower glycine levels.

• Vitamin B6 is needed to convert 3-phosphooxypyruvate to serine, and then to convert serine to glycine, so vitamin B6 deficiency could lower glycine levels.

• Tetrahydrofolate, the unmethylated form of folate (vitamin B9), is needed to convert serine to glycine, so folate deficiency or the trapping of folate as methylfolate due to B12 deficiency, could hurt glycine status.

• Excess methionine leads to the methylation of glycine. Removing the methyl groups from glycine requires iron, riboflavin, and unmethylated folate. Thus, excess methionine from eggs, dairy, and muscle meat, or deficiencies of iron and riboflavin, could also lower glycine status.

• Methylfolate is the off-switch for the methylation of glycine, so a deficiency in synthesizing methylfolate could lower glycine status. This requires riboflavin, niacin as NADPH, thiamin, calcium, magnesium, glucose, and ATP. The role of ATP in turn opens up the door to the importance of virtually every other nutrient and a host of genetic impairments in energy metabolism.

• Nutritional deficiencies or genetic impairments in any coenzyme-A-requiring pathway (fatty acid oxidation, pyruvate dehydrogenase, branched-chain amino acid metabolism, for examples) can lead to CoA sequestration, which is resolved by peeing out glycine conjugates of the CoA-sequestering metabolic intermediates.

• Benzoate is used as a preservative and in various pharmaceuticals such as acne cream, and leads to the loss of glycine in the urine during its detoxification.

• Hyperammonemia could lead to the loss of glycine in the urine as a way of removing excess nitrogen from the body.

• Glycine is most abundant in skin and bones, and low in other proteins. That we no longer eat nose-to-tail is a reason most of us run low in glycine.

How to Get More Glycine

A simple way to test whether glycine helps dampen an exaggerated startle reflex is to supplement with glycine, gelatin, collagen, or bone broth.

Roughly 3 grams out of every ten grams of gelatin or collagen is glycine. Roughly 3 grams of glycine are obtained from each cup of well-gelled bone broth.

3-5 grams of glycine per meal have been used for stabilizing blood sugar, 3 grams before sleep have been used to lower core body temperature and promote better descent into deep sleep, and 60 grams of glycine have been used in schizophrenia. 15 grams of gelatin containing approximately 5 grams of glycine has been used to stimulate collagen synthesis in joints prior to exercise.

If you remove schizophrenia as the outlier and sum up the other uses you could arrive at just over 20 grams of glycine per day. So we might say that 3-20 grams is the “normal” therapeutic window while 60 grams is the maximal dose shown to be safe.

Adverse Effects of Glycine

Excess glycine generates more NADH than glucose so could conceivably worsen a respiratory chain problem. This could be shown if glycine increases morning waking lactate, which you can test at home with a NovaBiomedical Lactate Plus. Studies show it does not cause hypoglycemia, but anecdotally some people have reported it doing so. Glycine could destroy someone’s health if they have a rare genetic defect in glycine cleavage.

Glycine conceivably could raise oxalate levels in some people, and this is more likely to happen in response to bone broth, gelatin, or collagen. This can likely be prevented by getting 3 milligrams of vitamin B6 for every 100 grams of protein.

Related Testing

Testing for the bullet point list of conditions that could lead to poor glycine status should include a Genova Methylation Panel, a Comprehensive Nutritional Screening, and a Comprehensive Screening for Energy Metabolism.

Have You Been Startled?

Have you found yourself excessively started? Have you tried glycine? Has anything else worked? Let me know in the comments!

Disclaimer: I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences. Please do not make any changes to your diet, supplements or medications based on this article and discuss any changes you wish to make with your doctor.

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