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Sleep and Neurotransmitters

Problems with getting a good night’s sleep is something we encounter a lot in our clinic.  Our stressful and busy lives, relationship problems, 24-hour society, constant stimulation, irregular sleeping patterns, shift work, poor diets, poor methylation, EMF effects and blood sugar problems all effect our quality of sleep.  And if we don’t sleep, we don’t heal, regenerate and replenish.  Our hormones start going out of balance, we start putting on weight and age very quickly.  There are many neurotransmitters involved in the sleep-wake-cycle and this post is limited to looking at them.  Keep in mind that there are many other factors that can influence sleep quality such as infections and blood sugar which we’re not going into detail here.

Neurotransmitters that Keep You Awake



Yes, it is not just about allergies.  Histamine has been included here because it stimulates the release of serotonin, dopamine and norepinephrine from the hypothalamus.  This means it should really be included in both inhibitory and excitatory, so we’ll leave it here for the moment.  Downregulations in HNMT and MAO will slow down the breakdown of intracellular histamine.  Balance is the key.  Suspect high histamine when there is asthma, eczema or any other hypersensitivity reactions involved.  Reducing high histamine foods may help to some extend or having vitamin C and quercetain before bed.


Norepinephrine (NE)

NE goes up in response to stress, but is also involved in cortical arousal and is at its lowest level during REM sleep.  It suppresses MCH (see below) and makes you more attentive to stimuli, like a young mum who is having trouble sleeping because she’s constantly listening for unusual noises from her baby and light sleepers who can suddenly wake up alert.  NE should be low when you go to bed (bedtime rituals and not too much stimulation) and almost absent during stage 3 delta and stage 4 REM sleep.

NE also increases the turnover of phosphoinositide in the cerebellum and cortex.

  • Phosphatidylserine
  • Omega 3
  • Adenosine
  • Herbs – Californian poppy



Dopamine boosts your energy, makes you focused, makes you feel good and keeps you awake.  Amphetamines, diet pills and ritalin (ADD drug) all increase dopamine levels and may interfere with your sleep.  Downregulation of SULT, COMT and MAO B enzymes won’t help either.


Epinephrine (E)

Adrenaline does not need much explanation.

  • Californian poppy


Orexin (Orx)/Hypocretin (Hcrt)

Orx is a neuropeptide involved in wakefullness (too much Orx), narcoplepsy (failure to express Orx), emotions and eating  Orx needs to be balanced for healthy sleep patterns.  Orx is stimulated in the presence of movement and increased muscle tone, when we are active during the day.  Orx, similar to MCH needs bursts of spikes to be released, unlike GABA or glutamate where single spikes are enough for its release.

High ORX = positive emotion and wakefullness

Low ORX = pain and wakefullness



Cortisol should be higher in the morning than the evening.  I cannot tell you how many times I’ve seen the reverse.  You want to wake up feeling energized and refreshed (high cortisol) and by evening want to feel calm and relaxed (low cortisol).  But we wake up feeling tired, struggle to get out of bed, plotter along during the day, and at night have trouble sleeping because we’re too stimulated.  This is an abnormal cortisol response.

  • Phosphatidylserine
  • Omega-3
  • Herbs – Rhodiolla, Withania, Holy basil



Glutamate is an excitatory neurotransmitter that keeps you focussed and alert but also keeps you awake.  Typically high when you feel you can’t switch your mind off (sometimes in combination with histamine) or suffer from restless leg syndrome.  Glutamate converts to GABA via GAD enzymes, so GAD polymorphisms or downregulation may be a reason for an imbalance between glutamate and GABA.  Because glutamate activates the NMDA receptors, anything that downregulates these receptors will negate the effect of too much glutamate.

  • Taurine
  • N-acetyl cysteine (cysteine however is excitatory)
  • Magnesium
  • Adenosine
  • Theanine
  • Lithium
  • Avoid yeast and MSG
  • Avoid artificial sweeteners containing aspartame


Neurotransmitters that Get You To Sleep


Also known as the ‘happy hormone’ it puts you in a good mood, helps you to relax, and converts to melatonin which is another neurotransmitter important for sleep.  Technically serotonin promotes wakefullness by inhibiting MCH (see below), but we’ve included it in this section because depression and sleeping disorders often go hand-in-hand.

Serotonin levels are affected by stress, infections (upregulation of IDO), blood sugar swings or not having enough carbohydrates at dinner time.  It is at its highest during wakefulness and helps to maintain cortical arousal but is at its lowest level during REM sleep.  Unlike NE it suppresses distraction from stimuli and is very important to get you to sleep but drops off during sleep.

Prostaglandins E1 and D2 (PGE1 & PGD2) will promote sleep by supporting serotonin activity in the brain.

  • 5-HTP
  • Vitamin B3 (if upregulated IDO)
  • Omega 3 (more EPA)
  • Blood sugar regulation
  • Treat infections or inflammation



This neurotransmitter is very effective at getting you to sleep but not necessarily to stay asleep.  It needs SAMe (methylation) and serotonin (see above) to be produced.  It is very much affected by stress, shift-work, jet-lag, too much light in the evening and using electronics (TV, tablets, kindle, mobile phones – essentially blue light).

  • 5-HTP
  • SAMe
  • Vitamin B5
  • Melatonin (prescription – slow release sublingual is best)
  • Blue-light blocker glasses
  • No electronic stimulation after 7pm
  • Keep room temperature at night below 22ºC


Melanocyte Stimulating Hormone (MSH)

MSH is a pituitary hormone that is often low when mold or Lyme disease is involved.  If this is low it affects sex hormones, moods and how well we control inflammation.  Lower endorphins will dramatically impair sleep.

  • Treat mold or Lyme if applicable
  • Keep room temperature at night below 22ºC


Melanin Concentrating Hormone (MCH)

MCH neurons are controled by NPY-neurons in the arcuate nucleus.  They are most active during sleep as it increases delta brain waves and GABA release.  It gets you into REM sleep faster and keeps you there longer.  MCH levels seem to increase during and after eating which could contribute to feeling drowsy after a meal, ready for a nap.  Reasons for this include MCH’s role in suppressing glutamate (wakefullness and learning) and stimulating GABA release.  It is also released in response to lack of movement or muscle tone.  So if you’re lying still in bed and still can’t fall asleep, then MCH is not firing properly.  MCH, similar to ORX needs bursts of spikes to be released, unlike GABA or glutamate where single spikes are enough for its release.

Downregulation of MCH is associated with weight loss, increased metabolism and lack of sleep whereas overexpression of MCH is associated with sleepiness, obesity, depression and inflammatory bowel disease (colonic inflammation).

Keynotes:  Eat more regularly



As mentioned, GABA is made via the GAD enzyme from glutamate and other cofactors.  Any deficiency in cofactors or downregulation of the GAD enzyme will affect GABA and thus sleep quality.  GABA is like our natural valium (without the side-effects) and does NOT cross the blood brain barrier (BBB).  If you take GABA as a supplement and you feel better (which many do), then you have a leaky BBB.

Keynotes:  Mitochondrial dysfunction 


Neurotransmitters that Keep You Asleep


GABA seems to work not by directly inducing sleep, but rather by suppressing other excitatory neurotransmitters such as glutamate, norepinephrine and epinephrine.  During stage 1 – 4 of non-REM sleep all neurotransmitters start to decrease.  If they don’t and you still feel alert, then you may not be producing enough GABA.

This is when some may turn to alcohol, opioids or tranquilizers as they suppress excitatory neurotransmitters and increase GABA concentrations in the brain.  It’s a much better idea to rather get your GABA production going again.

  • GABA
  • P5P (Vitamin B6)
  • Zinc



Acetylcholine increases cortical arousal during the REM phase and is a fascinating neurotransmitter in that it both inhibits MCH (which should interfere with sleep) but yet gets you into a deep sleep.  During stage 5 REM sleep you experience rapid eye movement and vivid dreams, but also lose the ability to move (or skeletal paralysis).  Sleepwalking will usually occur in stage 3 and 4 of non-REM sleep just before the acetylcholine surge.

When ACh is high, NE and serotonin is low (during sleep that is).  At the end of REM norepinhephrine and serotonin levels increase again which is why you are more likely to wake up at the end of REM sleep.  This is when you’ve just had a vivid dream or nightmare and then wake up startled or alert and struggle to get back to sleep again.

Night terrors often affect young children and occur during stage 4 of non-REM sleep just before REM.  The symptoms of night terrors (sweating, rapid breathing, rapid pulse) match cholinergic activation.



Other Factors Involved in Sleep



Sleep and thermogenesis are strongly linked.  If poor sleep quality becomes a chronic problem the forebrain starts to lose the ability to regulate body temperature.


Thyroid Function

There was an interesting study that showed diets low in selenium had a much higher turnover of dopamine and serotonin with increases in norepinephrine and high cortisol.  It would make sense as selenium deficiency is linked to higher reverse T3 levels linked with high cortisol.  This shows the clear link between thyroid, adrenals and sleep.  If you have low selenium you’ll have lower T3 (active thyroid hormone) and higher rT3 with higher cortisol and higher norepinephrine which will overstimulate you or create anxiety issues.  The decrease in serotonin means less melatonin which will affect the ability to fall asleep.  Since brain inflammation is a key factor in depression and sleeping problems we can see how selenium would also influence this by reducing oxidative stress in the brain.


Upregulated CBS enzyme

CBS stands for Cystathionine Beta Synthase and can be upregulated for various reasons.  Either directly through a genetic polymorphism – CBS 699 (CT/TT) – or due to increased oxidative stress in the body (infection, toxicity, etc.).  There is some controversy around whether it is significant or not, but I’ll mention it here as I can recongize its role in this context.  CBS upregulations are associated with the following:

  • High cortisol
  • High glutamate
  • High ammonia
  • Low glutathione
  • Increased inflammation

All of these tie in with depression and insomnia.  In my opinion I don’t think the genetic polymorphisms associated with this gene upregulation holds much weight, but I certainly have seen this in those with oxidative stress and gut dysbiosis.  So in short, it’s epigenetics, not genetics.



I’m mentioning inflammation here (it is not a neurotransmitter) because this is a common cause for keeping people awake at night and I think it’s important to understand why.  Inflammatory factors such as prostaglandins are released in response to infections or food intolerances.  Prostaglandins E2 and F2 (PGE2 & PGF2) strongly inhibits serotonin release which will make it very hard to fall alseep and also coincides with depressive disorders.

Keynotes:  Eliminate problematic foods and treat infections 


Circadian Rhythms

All these neurotransmitters and brain chemicals are secreted and released in phases and rhythms.  The body has a very intelligent build-in circadian clock that regulates all of these messengers that tells us when to sleep, wake-up, eat, etc.  It is regulated by the Suprachiasmatic Nucleus (SCN) in the hypothalamus that responds to light and dark signals.  Light will delay the release of melatonin and thus interfere with sleep.  Blue light from electronic devices (phones, tablets, laptops, TV screens) also interferes with melatonin release which is why you should stop using electronic devices after 7pm at night.  At the time of writing there is also a really cool free app called Twilight which can be installed on an android or iphone, and F.lux for laptops and computers.  It detects your location (time zones) and towards the end of the day it reduces the blue light on the device.

Different age groups also experience natural differences in their circadian rhythms as babies and older people spend more time sleeping and teenagers experience a delay in melatonin release at night.

Keynotes:  Avoid blue light late at night.  Get into the sun during the day.  Create good sleeping habits.



All of these neurotransmitters discussed above can be tested for.  When I mention SAMe, I’m not necessarily referring to SAMe as a supplement as I prefer to improve the body’s own production of SAMe which requires diferrent strategies in different people.

There are many herbs and nutrients that can influence these neurotransmitters.  Also, biochemistry is never this simple or 2-dimensional.  These neurotransmitters will influence and interact with each other as well as with other hormones.  When you change one of them, it will have a flow-on effect and something else will change as well.  That’s just the way the body works.  Most of the time it’s just about getting one neurotransmitter into balance that solves the issue.  Other times it’s a complete imbalance that needs to be restored with some lateral thinking.


If you need guidance in the treatment of this or any other condition, please make an appointment with one of our practitioners.

This article is for information purposes only.  Please refer to our Medical Disclaimer policy for more information.  The opinions expressed here represents the author’s and not necessarily those of Realize Health.  In addition, thoughts and opinions change from time to time due to updates in research and as a necessary consequence of having an open mind.  Views expressed in out-of-date posts may not be the same to those we hold today.



Neurotransmitters and Sleep

Major neurotransmitters involved in the regulation of sleep-wake cycle

Histamine in the regulation of wakefulness

Low selenium diet increases the dopamine turnoever in prefrontal cortex of the rat.

Fish consumption, sleep, daily functioning, and heart rate variability

The Role of Hcrt/Orx and MCH Neurons in Sleep-Wake State Regulation

A Physiologically Based Model of Orexinergic Stabilization of Sleep and Wake

Melanin-Concentrating Hormone:  A New Sleep Factor?

Lithium increases melanin-concentrating hormone mRNA stability and inhibits tyrosine hydroxylase gene expression in PC12 cells

Author Info

Elizma Lambert

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