Glycine Guide for Sleep and Mental Health

May 15, 2021

With sleep research, it's a bit like the spoof on the Brady Bunch.

"Marsha Marsha Marsha!"

Just replace that with GABA GABA GABA.

Yes, GABA is the linchpin for the process of sleep and we only need to look at sleep medications to confirm.

Benzos (valium, Klonopin, etc) directly boost GABA (see CBD versus benzos)

Sleep meds like Ambien? Boost GABA. (see CBD versus Ambien).

Of course, those build up terrible tolerance which leaves you worse off than where you started but we've covered that in depth.

There's a lesser-known player however which we want to shed more light on.

Glycine.

You know that point right before everything turns off with sleep? Deep in that process is glycine.

This deserves more research since sleep is such an issue these days.

Sleep is just the beginning of the research for glycine and mental health (although, they may share a common ground).

We'll have to hold off on effects for collagen, diabetes, and liver function, etc.

But we will cover these areas:

What is glycine
How does glycine work in the brain
How does glycine affect sleep
Glycine and body temperature for sleep
Glycine and anxiety
Glycine and OCD
Glycine and depression
Glycine and schizophrenia
Glycine and mental health
Glycine and glutathione (detox system)
Glycine and brain inflammation
Are there side effects to glycine
How much glycine in research
CBD and glycine

Let's get started.

What is glycine

Simply put, glycine is the building block of our proteins.

It's the simplest amino acid and provides the base for many other proteins and pathways throughout the body and brain.

It's the largest constituent of collagen which makes our skin, bones, and ligaments.

There are many different pathways for glycine but we're going to focus on how it works in the brain and nervous system.

Here's where it gets interesting.

Glycine actually has two opposing roles:

Glycine is a powerful inhibitory (brake pedal) driver...second only to GABA
Glycine is a co-player for our primary excitatory (gas pedal) pathway with glutamate

Talked about mixed messages.

As a neurotransmitter, glycine both stimulates and inhibits cells in the brain and central nervous system, affecting cognition, mood, appetite and digestion, immune function, pain perception, and sleep.

https://www.psychologytoday.com/us/blog/sleep-newzzz/201902/4-sleep-benefits-glycine

The effects on mental health mainly come from these two results so let's dig a little deeper.

How does glycine work in the brain?

Let's first look at the calming side….inhibitory.

Glycine exerts its inhibitory effects via specific glycine receptors (GlyRs)2 that are highly enriched in the postsynaptic membrane.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504737/

So there are specific receptors on neurons that slow down activity. This is very similar to how GABA works.

So why have both if they do the same thing?

GABA is more prominent in the brain while glycine is more prominent in the spinal cord and brain stem (the middle ground between the brain and spinal cord).

Basically, glycine slows things down and we should see the effect from this for related issues:

Sleep
Anxiety
OCD
Repetitive thoughts

We'll look at those below.

Also, glycine calms immune response (again, inhibitory) and this is important for brain inflammation which we'll look at with stroke below.

Here's the deal...glycine can be thought of as the master protein architect so it's intimately involved in so many different pathways (and other proteins).

This is where we get a polar opposite effect with glutamate, our main "gas pedal" in the brain.

Interestingly, for the glutamate receptor to "turn on", it also needs glycine as a secondary key!

This is the NMDA receptors and it comes into play with schizophrenia, autism, and other developmental diseases.

In fact, early trauma/infection can ramp up inflammation and as a result...glutamate with ties to every mental health issue!

So, glycine is a switch hitter for both the "on" and "off" switches in our brain depending on need.

On top of this, it's a key player in both the detox process (glutathione) and the anti-inflammatory process in the brain.

See CBD and oxidative stress or CBD and neuroinflammation to learn why this is so important for mental health.

To really see how this all works, we have to drill down into specific issues since glycine is such a building block element.

We'll start with our favorite...sleep.

How does glycine affect sleep?

Let's first start with the top-level effects and then drill down into the newly discovered mechanism:

In subjects given glycine, the VAS data showed a significant reduction in fatigue and a tendency toward reduced sleepiness.

https://pubmed.ncbi.nlm.nih.gov/22529837/

This was a study on healthy people with restricted sleep...sound like someone you know?

Interestingly, sleep quality was better. Sleep started faster. Most importantly, fatigue during the daytime was reduced and that's a sign of quality sleep.

So...what is driving this?

Here's the new research.

First, let's introduce you to a very special part of the brain, the suprachiasmatic nucleus (SCN).

In the brain, a small group of hypothalamic nerve cells, the suprachiasmatic nucleus (SCN), functions as a master circadian pacemaker controlling the timing of the sleep-wake cycle

https://pubmed.ncbi.nlm.nih.gov/18032104/

This is the "clock" of sleep and wake states. People with lesions here can sleep but the timing is all over the place.

Glycine's role?

The Sleep-Promoting and Hypothermic Effects of Glycine are Mediated by NMDA Receptors in the Suprachiasmatic Nucleus

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397399/

This is interesting since NMDA is the excitatory receptor (remember glutamate). It just means "turning on" this pathway which is key for the machinery of our sleep patterns.

More recent studies have actually found the "switch" for sleep itself, but that is triggered more by GABA than glycine.

In a new study published in Nature Communications today, Saper and colleagues demonstrate in mice that these cells – located in a region of the hypothalamus called the ventrolateral preoptic nucleus (VLPO) – are in fact essential to normal sleep.

https://neurosciencenews.com/sleep-switch-9973/

The VLPO - an "on switch" for sleep.

Lesions there are very pronounced in effect:

Lesions of the ventrolateral preoptic nucleus result in marked sleep fragmentation due to difficulties in maintaining sustained sleep, as well as a decrease in total sleep time (Lu et al., 2000)—a pattern similar to that seen in aging and Alzheimer’s disease

https://academic.oup.com/brain/article/137/10/2847/2847696

So...glycine for the clock of sleep and GABA for the switch of sleep.

Interesting, CBD is a feedback supporter for both! More on that below.

There's another interesting quirk with glycine that ties into sleep...temperature!

Glycine and body temperature for sleep

In order to sleep well, your core body temperature needs to drop significantly:

It is suggested that a rapid decline in core body temperature increases the likelihood of sleep initiation and may facilitate an entry into the deeper stages of sleep.

https://pubmed.ncbi.nlm.nih.gov/9322266/

In fact, this process gets slower and later as we age (hence the sleep issues).

Some types of insomnia are tied to a mismatch in this temperature piece and sleep.

So...what does this have to do with glycine?

A recent study of the effects of glycine as a supplement showed it triggered a drop in body temperature and at the same time helped people both fall asleep more quickly and spend more time in REM sleep.

https://www.psychologytoday.com/us/blog/sleep-newzzz/201902/

Think of this as an associated piece of the "clock" maintenance function of glycine by itself.

We have a full review of CBD and sleep.

Recent studies have shown in MRI studies that the brain looks the same after sleep deprivation as in extreme anxiety!

Let's go there now.

Glycine and anxiety

We've covered GABA's primary effect for anxiety.

Glycine has a different role which directly supports a calming effect.

This is especially pronounced for panic attacks and physical effects of anxiety which can be self-referential (you become more anxious because you feel your heart pound, etc).

Remember that glycine is a major "brake pedal" in the spinal cord and brain stem so this makes sense...signals to and from the body!

Let's unravel this piece first.

It turns out that glycine counters the effect of adrenaline (norepinephrine). Adrenalin is key to the fight or flight response and we'll focus on flight.

Panic. Fear.

That's the sweating, heart pounding, eye's wide-open effect.

When an individual experiences anxiety or panic, NE is released and creates feelings of anxiety and panic. Glycine antagonizes the release of NE, thus mitigating anxiety and panic and feelings of over-arousal.

https://hospitalnews.com/nutritional-treatments-to-combat-anxiety-disorders/

Remember...this physical response to fear feeds back on itself and triggers other responses in the brain.

Speaking of which, let's introduce the habenula.

The what?

It's just the seat of dread in the brain.

The brain structure, known as the habenula, activates in response to negative events such as electric shocks, and they may help people learn from bad experiences.

https://time.com/3048559/brain-senses-dread/

We covered this area in our CBD for panic attacks and CBD and negative thoughts.

So...glycine's effect there.

From a study with alcohol addiction:

Activation of GlyRs reverses LHb hyperactivity, alleviates aberrant behaviors, and reduces alcohol intake, thus highlighting the GlyRs in the LHb as a potential therapeutic target for alcohol-use disorders.

https://pubmed.ncbi.nlm.nih.gov/31254534/

To translate (please!), when glycine receptors are activated, hyperactive habenula activity goes down which had positive effects on alcohol abuse.

This is a huge deal! See CBD and alcohol addiction or CBD and addiction.

There's a known effect on CBD and "fear extinction"...basically the ability to forget bad memories or feelings.

We can now firmly place this effect in the glycine camp.

For more on the pathways of anxiety.

Let's turn to other diseases tied to a mismatch between the calming and exciting pathways of our brain.

Glycine and OCD

We've covered CBD and OCD in detail with a heavy focus on GABA.

A study looked at people with untreatable (called refractory) OCD with the following effects:

Those receiving glycine (n = 5) experienced a mean decrease of 6.04 points in Y-BOCS score, compared with a 1.00 point decrease for those receiving placebo (n = 9).

https://www.sciencedirect.com/science/article/abs/pii/S0022395608002379

This is a big deal...6 points out of a total of 40.

6 points can drop you into a different category (say from severe to moderate).

OCD is characterized by excessive glutamate and excitatory effects in the brain.

GABA has the bulk of the responsibility of keeping glutamate in check but glycine also plays a role there.

Also, look at the research on NAC and OCD which is powerful.

Let's turn to depression and glycine.

Glycine and depression

We've covered depression in-depth at our CBD and depression review.

For glycine, new research is coming to light.

First, the risk factor:

Significantly lower plasma glycine values and a higher serine/glycine ratio were observed in the depressed group.

https://www.sciencedirect.com/science/article/abs/pii/0924977X9500033L

Why would a calming break pedal figure into depression?

The more obvious effect is this:

Oral administration of glycine increases extracellular serotonin but not dopamine in the prefrontal cortex of rats

https://pubmed.ncbi.nlm.nih.gov/21414089/

Serotonin is AN immediate chemical messenger for depression as it boosts BDNF, our brains' fertilizer, and directly manages mood (all human behavior really).

Check out CBD and serotonin to learn more.

The prefrontal cortex is THE area for depression. It's the part right behind your forehead which makes us...us!

If it shrinks due to stress, hyperactive immune response, alcohol, drugs, medications, etc...depression is the result.

In fact, we've dived deep into this area with the following:

Look...of the million-plus words we wrote, BDNF may be the most important player for mental health including depression.

A brand new study looked at glycine and NAC (research here) effect on BDNF for older people:

GlyNAC could also be having a direct effect in the brain as seen by a significant increase in the diminished levels of the brain biomarker BDNF

https://onlinelibrary.wiley.com/doi/full/10.1002/ctm2.372

The results of allowing this to drop as we get older (see CBD and dementia):

DNF is involved in the preservation of memory, synaptic plasticity, and maintenance of neuronal networks,64, 65 and lower plasma levels of BDNF are associated with lower cognitive test scores and mild cognitive impairment.

https://onlinelibrary.wiley.com/doi/full/10.1002/ctm2.372

One component of schizophrenia is depression, low effect, and the so-called "negative" symptoms. Let's go there now.

Glycine and schizophrenia

There's a known glycine/serine pathway issue with developmental diseases like schizophrenia.

It goes deeper than that.

First, some of the preliminary studies:

A significant 34% reduction in negative symptoms was observed during glycine treatment.

https://pubmed.ncbi.nlm.nih.gov/11806864/

34%!! Seriously? From a simple protein?

The negative symptoms are depression, low mood, social isolation, etc.

What's going on here?

It's a question of oxidative stress in the brain.

Glycine (in the form of betaine) is a powerful antioxidant in the brain:

They found that betaine not only improved cognitive deficits and behavioral abnormalities, it also reversed oxidative stress at the molecular level.

https://www.sciencedaily.com/releases/2019/06/190626124940.htm

This goes back to the "inflamed brain" premise for most of the mental health which is quickly gaining ground.

Remember that early trauma/infection (even in utero) can ramp up inflammation later in life!

A study looked at CBD's effect on the brain following alcohol exposure:

Gly treatment reduces ethanol-induced oxidative stress and neuronal cell loss in SH-SY5Y cells and in the developing rat brain.

https://pubmed.ncbi.nlm.nih.gov/27058626/

The tie-in with schizophrenia?

Many studies show that oxidative stress is a pathophysiological mechanism of schizophrenia.

https://jpbs.hapres.com/htmls/JPBS_893_Detail.html

We'll go deeper into this with the glutathione angle below to see glycine's specific role.

It's also why NAC is such a powerful player.

Glycine and mental health

We touched base on specifics but there are key pathways tied to every mental health and neurodegenerative issue directly impacted by glycine.

The big ones are these:

Glycine and oxidative stress
Glycine and excessive glutamate
Glycine and immune response
Glycine and serotonin
Glycine and BDNF

These are monster players in mental health and brain function.

Just a quick review (see CBD and mental health).

Glycine and oxidative stress

We just covered this but oxidative stress is literally a poison to brain function when not kept in check.

Recently, oxidative stress has also been implicated in depression, anxiety disorders, and high anxiety levels.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763246/

Glycine is a major piece of our primary anti-oxidant...glutathione.

We covered CBD and glutathione or CBD and oxidative stress in detail for mental health.

Glycine and excessive glutamate

Glutamate, when excessive, is toxic to the brain.

Glycine has a dual role with glutamate:

It has both an inhibitory effect (counter to glutamate) and a supportive role for glutamate (the NMDA receptor piece).

Glutathione is a powerful sink for excess glutamate as well.

Why is any of this important?:

Specifically, central system glutamate dysregulation has been associated with symptoms of anxiety, posttraumatic stress, obsessive-compulsive disorder (OCD), mania, depression, and psychosis [5, 31], with the strongest evidence for glutamate's role in schizophrenia

https://www.karger.com/Article/Fulltext/496294

This piece is really fascinating with immune response (remember, early trauma/infection).

Glycine and immune response

Neuroinflammation - the inflamed brain theory for mental health.

Every mental health issue we've looked at has a marked increase in brain inflammation.

Every one.

We did a monster review of why the immune system is the future of mental health.

We'll cover the finer points of this effect below but there's another interesting piece.

Glutamate!

Look at what happens with inflammation in our brains from the immune response:

activated microglia trigger the elevation of extracellular L-Glu through their own release of L-Glu, and astrocyte L-Glu transporters are downregulated as a result of the elevation of astrocytic intracellular L-Glu levels, causing a further increase of extracellular L-Glu.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575281/

We'll translate. Microglia are the brain's main immune commanders.

When triggered (inflammation), they release glutamate (the toxin when excessive above).

This triggers a nasty loop with astrocytes (another brain immune player) to cause more glutamate release!

This may be key to why early exposure to infection (bacterial or viral) even in-utero can raise mental health risks later in life.

See CBD and autism or CBD and schizophrenia for direct examples (also bi-polar and OCD).

Glycine and serotonin

We already noted glycine's effect on serotonin, our master regulator of mood and human behavior.

It's also our primary stress response buffer (key to mental health).

We noted how glycine boosts serotonin above.

Net-net…

In particular, glycine helps the body make serotonin, a hormone and neurotransmitter that has significant effects on sleep and mood.

https://www.psychologytoday.com/us/blog/sleep-newzzz/201902/4-sleep-benefits-glycine

And direct effects:

Both glycine and d-serine significantly increased extracellular 5-HT levels for 10 min, whereas dopamine levels remained unchanged

https://pubmed.ncbi.nlm.nih.gov/21414089/

5HT is serotonin.

Interestingly, serotonin is the main precursor to our next benefit.

Glycine and BDNF

Remember….this is the ultimate goal with mental health from all the research we've come across.

In the study of young and old people, look at the impact on BDNF from glycine/NAC supplementation:

Young baseline was 36 for blood plasma levels of BDNF
Old baseline was 21
Old after NAC/GLY was 31 after 24 weeks

Goodness! It almost brought it up to that of young people!

This is so important for age-related cognitive decline and definitely mental health.

Again…

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that modulates neuroplasticity in the brain, and is one of the most widely investigated molecule in psychiatric disorders.

https://www.sciencedirect.com/science/article/pii/S2319417020300056

Okay...let's turn to glutathione since glycine has such a direct impact.

Glycine and glutathione (detox system)

Here's the interesting piece…

Glutathione, our main detox player is made of:

Cysteine (hence the NAC angle - the "C")
Glutamate
Glycine

Goodness! Here's the key piece with glycine (and with cysteine):

Dietary Glycine Is Rate-Limiting for Glutathione Synthesis and May Have Broad Potential for Health Protection

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855430/

This is so important...basically, our levels of glutathione is limited by our levels of glycine.

Glutamate is so readily available that it's not the issue.

Cysteine and glycine are the limiting agents.

If you look at the benefits of NAC for mental health (review here), it's the same powerful story.

Glutathione is outgunned with many if not all mental health issues.

By the way, alcohol eats up glutathione (see CBD versus alcohol or Is CBD better than alcohol).

Hence the liver and brain damage associated.

Glutathione is your new best friend for brain health and glycine is a critical piece of this puzzle.

Glycine and brain inflammation

We already covered some of this above but let's dig deeper.

Generally speaking, glycine has a calming effect on the immune response which matches its other inhibitory effects.

Glycine has inhibitory effects on immune cells, including macrophages, monocytes, neutrophils and lymphocytes.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1665071/

That all makes sense.

So...what's the practical effect of this.

We'll translate this but results from studies on essentially a poison being added to the brain:

Our findings demonstrate that Gly-mediated deactivation of the JNK signaling pathway underlies the neuroprotective effect of Gly, which reverses D-gal-induced oxidative stress, apoptotic neurodegeneration, neuroinflammation, synaptic dysfunction, and memory impairment.

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01989-w

Goodness...what does that mean?

Okay...glycine calmed a key inflammatory pathway with the following results:

Reduction in oxidative stress
Reduction in cell death (apoptosis)
Reduction in brain inflammation
Reduction in damage with signaling in the brain
Reduction in memory issues

Check out CBD and neuroinflammation to learn why this is so important to mental health.

Okay….why do we keep referencing CBD and why are we even talking about glycine when our primary research is on CBD?

Glad you asked.

CBD and glycine

Check out the list of pathways that CBD affects here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345356/table/T1/

Under the CBD heading, you'll see three results on the right:

GlyR - positive allosteric modulator

That basically means that CBD supports the glycine receptor pathway just like it does for GABA.

The point is that it doesn't just boost it in one direction (called an agonist).

For example, benzos (see CBD versus benzos) boost GABA in one direction and the tolerance is brutal not to mention the spike to dopamine (addiction).

Basically, the body pushes back against this outside influence and actually reduces natural GABA levels.

This quickly becomes a nasty cycle of decreasing GABA and the anxiety, insomnia, etc that follows.

The positive modulator basically means that it supports Glycine levels when low.

This really is the beauty of how CBD works.

We see its effects across many pathways such as:

Healthy cell with low inflammation - CBD has no effect
Healthy cell with high inflammation - CBD reduces inflammation
Cancerous or virally infected cell - CBD INCREASES inflammation

Read that back over - 3 different responses from 3 different initial states.

The last one makes sense once you understand that this is how our immune system kills wayward cells.

By the way...the "inflammation" in this example is….oxidative stress!

Chemo and radiation are just massive doses of oxidative stress that kill indiscriminately.

Otherwise, with GABA and glycine, we would see increasing CBD doses lead to sedation and worse.

We don't...even at doses up to 1500 mg.

So supplementing glycine and CBD together along with NAC could be powerful tools for mental health and sleep.

Check out CBD and GABA or NAC and mental health for more info.

One note...we focused on mental health and sleep while totally avoiding interesting research on metabolism, heart health, and collagen support.

Some practical questions.

Are there side effects to glycine

Glycine is very safe as a building block amino acid (simple form of protein).

Studies have used up to 90 grams of glycine per day over several weeks without serious side effects

https://www.healthline.com/nutrition/glycine

1 gram is 1000 mg. The usual dose comes in 1000mg capsules and the typical daily amount is 3-5 capsules (3-5 grams).

This is well below the 90 grams tested!

There are few side effects reported with a mild one for GI issues which probably is a function of reducing dosage and/or allowing the microbiome to adjust to glycine.

The only medication interaction we can find is with clozapine (antipsychotic) as glycine might reduce its effectiveness. This is usually with schizophrenia.

See the studies on CBD and schizophrenia by the way...very interesting. NAC as well.

What about dosage?

How much glycine in research

The typical use case is between 3-5 mg of glycine.

This partially depends on what it's being used for and its severity.

Glycine does not block tryptophan which is important and use for sleep is advisable since it's so tied into that process.

You can get glycine here.

There's no reported tolerance with long-term use of glycine which makes sense since it's a basic building block of protein that we typically need about 2-3 mg per day from the diet.

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