Neurotransmitters: progesteron on the brain

Just for funsies I was wondering about the relation between noradrenaline (NA) and progesteron in the brain. Any neurotransmitter interference there?

Boy! Did I hit the jackpot!
It’s only from one source and I haven’t had time to check out the source itself or other sources or research but if this is true it connects a whole lot of dots.

the source:

Progesteron and oestrogens claim serotonine receptors in the brain. Oestrogens promote the growth of these receptors, progesteron decreases it. This can account for some of the depressive feelings during PMS (post menstrual syndrome, occurring at least one week before the period, when oestrogens drop and leaves behind a field of serotonine receptors who’ve got nothing to feed upon).

Progesterone increases MAO activity, Estrogens decrease its functionality (!!)
Meaning Progesterone promotes excitatory neurotransmitters getting catabolized, broken down, whisked away.

People with progesterone deficiency have their brain bombarded longer by excitatory neurotransmitters? (it fits the symptoms of Estrogen excess)
How about people with progesterone deficiency AND a faulty MAO A enzyme? oooh boy….

Estrogens numbs the MAO enzyme, allowing the excitatory neurotransmitters to keep bouncing around in your head. People with natural high levels of these neurotransmitters are active, excited and happy (depending on their individual signature of the mix).
People who are low on these neurotransmitters (ADD people perhaps) get depressed when their Estrogen levels drop and Progesterone keeps egging on the break down of the few neurotransmitters they have. They would have very depressive PMS.

But it might be more complex than this. Balancing hormones teaches us that hormones are not like scales: add a little here and it will decrease over there. No, it is more complex.
Having higher levels of a transmitter makes its receptors more numb for it and makes the receptor for its antagonist more hungry. For example, taking more Progesterone enhances the level of Estrogen receptors. Making for more tender breasts during PMS, even though you are supplementing with higher levels of Progesterone than you ever had naturally.

Might a happy feeling come from Endorphines and not from the mix of high dopamine and progesterone supplementation?
Progesterone correlates to feeling at ease, calm (hello PNS). Not happiness per sé.

Another article from the same source kept me awake last night:

  • Estrogenen increase the serotonergic, noradrenergic and opioidergic activity in the brain. (grrrrr!)
  • Progesterone increases MAO slightly. Progesterone’s most profound neuronal effect, however, results from its direct effect on the neuronal membrane. Progesterone has an inhibitory effect on neuronal excitation, depressing neuronal firing.
  • one of Progesterone’s metabolites is called Allopregnanolone. This is een neuroactive steroid. Allopregnanolone hyperpolarizes neurons by potentiating GABA-mediated synaptic inhibition. It acts at a neurosteroid-specific site on the GABAA receptor to facilitate chloride channel opening and prolong the inhibitory action of GABA on neurons. Allopregnanolone is one of the strongest ligands of GABAA receptors in the CNS, with a potency similar to that of the most potent benzodiazepines (Valium etc) and approximately a thousand times higher than pentobarbitals. (sleeping pills)
  • brain activity of progesterone and allopregnanolone is not dependent solely on ovarian and adrenal production. It is made in the brain itself.


  1. Progesterone depresses neuronal firing.
  2. Its metabolite Allopregnanolone eggs on GABA activity (GABA is needed for REMsleep!)
  3. Allopregnanolone does the same as benzo’s do, the drug so many insomniacs turn to
  4. Allopregnanolone does what sleeping pills do a thousand times better
  5. Progesterone is made in the brain (what if my deficiency is expressed there too? Is it synthesized in the brain from cholesterol? How does this work?)


Just for a little bit.
It’s all those excited neurotransmitters you see. And not enough progesterone to depress neuronal firing.

I want more (to know about) Allopregnanolone.


PS a strong symptom of Progesterone overdose is sleepiness. Allopregnanolone would account for this, as it’s as potent as the strongest sleeping aids.

taking a Progesterone pill (100mg) is the one thing that gets me through the nigh and only during PMS time. Earlier in the cycle and I feel very very groggy the next morning.

PS2 on RisingPhoenix someone says that it’s oral Progesterone that gets converted to this Alloprgnanolone. Not so much the transdermal cream.


Sleep: noradrenaline (2)

I wrote: “I expect the activity in the noradrenaline brain network to change once the sleep waves change. I.e. when the sleep cycle changes so does the activity of the neuron network. I need to go look for studies that tell me wether its activity increases or decreases.
Based on my insomnia I expect it to increase. Leaving me with a surplus of noradrenaline bouncing around my head.”

But I found that noradrenaline falls before we get into REMsleep.

Prof. Mallick is very busy unraveling how noradrenaline and REMsleep are connected. He ties it to illness too. When we are REMsleep deprived, we get ill.

“My working hypothesis is that “one of the functions of REM sleep is to maintain the brain excitability (Mallick et al., 1993, 1994, 1999)” and therefore, REM sleep possibly serves house keeping function of the brain (Mallick and Singh 2011). My lab has been working towards understanding its possible cellular mechanism of action.”
This theory is very popular at the moment. Glia’s and sleep detox and stuff.

Prof. Mallick explains briefly on this page.

He links Glia-activity to Noradrenaline (NA):
“Further, the brain contains neurons as well as glia and both possess NaK ATPase. REM sleep deprivation induced increased NA stimulated neuronal NaK ATPase activity, while the glial enzyme activity was decreased. The opposite actions of NA on neuronal and glial NaK ATPase activity probably help maintain neuronal homeostasis (Baskey et al. 2009) (Fig. 4).”
(NaK ATPase is just the good old Natrium Kalium pump in every cell membrane. Sodium Potassium pump to American friends)

In his scientific research I read about the workings of glia. During sleep the cells of the brain shrink a little bit, giving room to glia and to the intercellular fluids. These two shuttle away debri and cell waste.
It is important that this all happens: the shrinking and the waste elimination.

He found that during nonREMsleep (the first five hours of my nights) there’s a continuous firing of neurons called REM-off.
Once they seize firing another set of neurons start firing, REM-on.
REMsleep commences.

The REM-off/on’s activities are governed by GABA (and Noradrenaline). During REMsleep GABA is high, deactivating the Lucus Coeruleus. PubMed source here.
As long as there’s GABA, there’s REMsleep. Onset is governed by cholinergic input from the Locus Coeruleus. PubMed source here (prof. Mallick)
(cholinergic = Parasympathetic nervous system!)

REM-off neurons are called norepinephrinergic. Meaning they have to do with the SNS.
When a brain is REMsleep deprived it’s NA rises, keeping the REM-off neurons firing, prolonging the REMsleep deprivation. Gaba inhibits those pesky REM-off neurons, giving REM-on a chance. PubMed source here.
Stay away from stress, children.

During a study of blocking adrenoceptors to determine interaction between neurotransmitters and sleep this was quoted:
“Also, a critical level of norepinephrine in the system was required for the generation of REM sleep, however, a higher level may be inhibitory.”
PubMed sourcs, prod.Mallick
So you need a little bit to get to REMsleep. But too much will prevent it.

There must be a system governing NA levels in the brain during nonREMsleep. When it’s time to go to REMsleep the NA level will drop/rise (?) to the right level to let REMsleep commence.
In my brain the target is overshot. The NA level rises so much that I don’t get to REMsleep. I get to wake.

I think I’m onto something. I’ll investigate further. What system, what influences it?
In the mean time I’ll make sure I don’t get up while I lie awake. Getting that second stint of sleep is important. Get all the REMsleep you can.

5 hours solid sleep, 2 hours awake, 2 hours of (crappy) REMsleep. It’s the best I can do at the moment.

Sleep theory: noradrenaline

I’m still looking for a sensible theory to account for my weird sleep pattern of insomnia after the 5h non-REM sleep part of the night.

At the moment I’m looking into the excitatory neurotransmitters because I found out the disposal system of these is a bit crooked in me. The enzyme responsible of breaking down (nor)adrenaline, dopamine and serotonin is called MAO A and I have an allele combination that makes it do its work veeeeeery slowly. Making me an upbeat, cheerful person by nature. Going into manic chattering when excited too much:

I found some tidbits I’m going to connect without knowing what I do.

I woke up after 5 hours of sleep. I lay there with my eyes closed, observing, and noticed that although my brain was ON my body was not. My body was heavy, warm, sleepy.
I tried to not get my brain any more excited than it already was (no lights on, no surfing, no worrying, no thinking up clever schemes, no planning). I did resolve to investigate another angle to this insomnia when properly awake: what if it’s not cortisol keeping me awake but something that’s only active in the brain?
Cortisol travels through the blood and should have effect all over the body. Maybe one of the excitatory neurotransmitters keeps its actions restricted to the brain?

Noradrenaline is both a hormone and a neurotransmitter. It’s made in the adrenals (not the same part that makes cortisol though) and released in the blood = hormone. And it’s made in the brain (in sections called Locus Coeruleus, in the brain stem) = neurotransmitter.
As a neurotransmitter it’s active in the central nervous system and sympathetic nervous system. As such it fires up the sympathetic nervous system, elbowing the parasympathetic system into submission.
The actions of norepinephrine are carried out via the binding to adrenergic receptors.

Locus Coeruleus, noradrenaline HQ

Wiki says: “Noradrenergic neurons project bilaterally (send signals to both sides of the brain) from the locus ceruleus along distinct pathways to many locations, including the cerebral cortex, limbic system, and the spinal cord, forming a neurotransmitter system.”
Does it say here that there’s a distinctive network in the brain for this neurotransmitter? Is there a web bringing it’s activity fast and furious into all parts of the brain?
yes it does

This network can be tested. Increase in activity can be measured. Data can be found!
They think this network is involved in decision making and in storing memories. There’s research on it (using rats I believe).

Noradrenaline (or norepinephrine) is synthesized in 3 steps:

  1. the aminoacid Tyrosine is hydroxylated into L-DOPA (by enzyme/gen Tyrosine Hydroxylase)
  2. L-DOPA is decarboxylated into Dopamine
  3. Dopamine is hydroxylated into Noradrenaline

Wiki: “Noradrenaline is the hormone and neurotransmitter most responsible for vigilant concentration in contrast to its most chemically similar hormone, dopamine, most responsible for cognitive alertness.[4]”

check. check. This is what I have in abundance, especially at night. This is also what places me on the other end of the spectrum from people with ADD, I believe. I wish we could barter and both end up in the middle.


 pic by Paul Turnbull

There’s a fourth step when fiddling with noradrenaline:

4. Noradrenaline is made into Adrenaline via methylation of its amino group.

It takes methylation to get rid of noradrenaline! Does this get hindered by the same dna-oopsies I have hindering the Methylation Cycle? This would account for huge amounts of noradrenaline lingering in the system, firing up the brain.

Although: would I want to trade noradrenaline for adrenaline in the middle of the night? I don’t think so.

Here’s the wiki link on how it is terminated or degraded. Need to read it myself and use its terms to dig through scientific papers.

On first scan I see I shouldn’t take cocaine since it inhibits uptake of noradrenaline. That’s good to know, I’ll inform my dealer.

What facilitates degradation in mammals? What is the usual half time?

“α-Methyltyrosine is a substance that intervenes in norepinephrine synthesis by substituting tyrosine for tyrosine hydroxylase, and blocking this enzyme.”
what’s this? can I buy this? cook it up myself?

“Vesicular transport modulators[edit]
This transportation can be inhibited by reserpine and tetrabenazine.[33]”
are these drugs?

A few inhibitors to the release of noradrenaline are named. And a few that stimulate it. Adrenaline causes noradrenaline. Stay away from stress, children.
This does explain a lot of my own experiences.

Tyrosine is found in eggs, nuts, meat and cheese. And we make it ourselves from Phenylalanine.
Cutting down on any of these food stuffs won’t do much good as the body choses how much it converts. It’s not particularly dependent on intake. Unless you really stop eating these as hard core veganists do. And they might well be happier and more zen because of it too.

 pic by Penny Mathews



They suspect that the network of noradrenaline in the brain is used to store memories.
They also found that in the nonREMsleep this network’s activity coincides with the waves that are visible on EEG. When the wave goes up, so does the activity in the noradrenaline network. When the wave goes down, so does the firing frequency. They suspect this is how mammals store memories during sleep.
Here’s the link to the study (rats).

To me it says that during nonREMsleep the system pulsates, in the same slow way as the sleep waves do. I expect this to change once the sleep waves change. I.e. when the sleep cycle changes so does the activity of the neuron network. I need to go look for studies that tell me wether its activity increases or decreases.
Based on my insomnia I expect it to increase. Leaving me with a surplus of noradrenaline bouncing around my head.

If I can pinpoint why it stays active I can experiment. Or I can start experimenting and use the outcomes to focus the theory better.
It might be that methylation into adrenaline doesn’t work properly or that the MAO A clean up crew is working with two hands tied behind its back. Or the degrading system doesn’t work very well. I’m going to investigate further the subjects I touched upon above.

Or I might figure out why the surplus noradrenaline becomes active in the first place. If I can decrease its release (by taking away the cause or by taking surpressing drugs) I might sleep through the night. It would illustrate that it’s indeed noradrenaline waking me up and keeping me awake.

Well, I’m still just theorizing here. But in theory it all makes sense and it all coincides with my own symptoms and data.

If this becomes a credible, logical train of thought I plan to test it out. (no idea how to test, yet)
At night I want to sleep, from nonREM to REM. So I can wake up and be cheerful all day.

Brain chem: double shot of MAO A, cream, no sugar.

There’s this enzyme called MAO A. It takes a neurotransmitter and slices it up for parts. The neurotransmitters it typically likes are the excitable ones: adrenaline, noradrenaline, dopamine and serotonine.

I have a faulty gene coding for this enzyme. One of the basepairs is double mutated. G codes for higher activity of this enzyme, T for lower. I have two T’s, my enzyme doesn’t work as well as it could.

Now before everyone runs over to dr.Wiki and starts talking about Brunner Syndrome and oversexed violent people, that research is about one family (albeit Dutch) and about a specific mutation that put the whole gene out of commission. My mutation involves a base pair that (I suspect) downregulates the gene and is actually quite common.

But I need to read loads more about it. I did some earlier today and got really excited. But now I’m too fogged to put it all together in a sensible way.
I’m going to put some things here anyway, just for funsies, and hope to come back to it later and sort it out.

 pic by David Schauer

Epinephrine doesn’t get cleared away at a normal rate. It pools up and as it’s an excitatory neurotransmitter, it bounces around in my synapses, making my head resemble a pin ball machine. This is actually how I have described my mental state and capacity for many years.

You know what’s that like, right?

 pic by Eziquel (zick) Boita

You’re wired, sharp, ready to move a mountain, fight a lion and kick some ass. Yeah baby! You are ALIVE!
It’s very akin to being over-caffeinated. Caffeine does indeed raise adrenaline.

This is what I felt like for 35 years. Apart from feeling ALIVE this is also Fight or Flight. This is feeling smart and on top of the world but at the same time wrecking the body because there’s no time or room for slow, healing processes.

While the (nor)epinephrine builds up and pools because the clean up crew is working with one hand tied behind their back, the body shuts down production of NE because there’s just too much. Then, when the NE eventually does get cleared away, there’s a gross shortage of the stuff.

Having your MAO A not work properly causes you to have all kinds of peaks and lows other people have not. In your mood. Mood swings!
I had noticed that my feelings had a more wide amplitude than those of my friends, classmates and mates at university. Also, they could swing really fast.

pic by Samuel Ascaso Piqueras

“Because the nerve circuits in the prefrontal brain regions, which are normally involved in attention, require high levels of dopamine and noradrenaline stimulation, reduced levels of these two neurotransmitters could potentially lead to the weakened regulation of attention and behavior observed in ADHD .”

“Methylphenidate, the active ingredients in Ritalin®, acts like a weak form of cocaine to increase dopamine and noradrenaline levels but tends to do it all over the brain sometimes resulting in unwanted side-effects such as nervousness, drowsiness, insomnia, suspicion and paranoia.”

“Norepinephrine, which is closely related to dopamine, is the main chemical messenger of the sympathetic nervous system. The sympathetic nervous system controls many automatic functions of the body, such as heart rate and blood pressure. The loss of norepinephrine might help explain several of the non-movement features of Parkinson’s, such as fatigue, irregular blood pressure, decreased gastric motility or movement of food through the digestive tract, and postural hypotension. ”

At the forums of I found a few others with this mutation and hearing how they live their lives makes all kinds of sense to me. They thrive on flat blood sugar levels. They too only need a morsel of a drug or supplement to notice its effect. They know about coffee.

It’s so nice to recognize! I have much to learn from them.

This mutation offers a sensible explanation for my sensitivity. Any jump in adrenaline has an after effect long after the event.

Because of the delayed decrease and pooling of the neurotransmitters it’s good to have an uneventful day. It also explains why the band of comfort with supplements and drugs is very narrow. Basically it explains why I am so ridiculously sensitive to things. The sensitivity my doctor compares to autistic sensitivity.

It seems cortisol has a balancing effect on (nor)epinephrine?

“The other two neurotransmitters that have been implicated as playing an important role in sleep are norepinephrine (NE) and serotonin (5-HT).”It might be that high NE invites a rise in cortisol. If Deep Sleep causes NE to rise and in my case uncomfortably high, cortisol might kick in to try and dampen it. But it’s too much and I wake up and lie awake, waiting for the cortisol to leave the system.

I read a piece about how at night the body plays pretend-inflammation because it needs to do certain things for which it needs the higher temperature. I do know brain temp rises. It isn’t actual inflamation. But an overly dramatic imune system might think so, causing cortisol to rise.

I have to reread it and try and understand but at the moment: brain fog.

A little more about MAO A. It sits on the X-chromosome. I have two faulty alleles. So my mother AND my father(‘s mother) gave me a faulty allele.

This means that my father has the same disfunction that I have, a homozygote, him having only one X-chromosome. And so does my brother. They must have the same peaks and lows in their adrenaline.

Well…..we ARE a family that comes across as being over-cafeïnated….
My whole family from father’s side does. We are smart, fast, ALIVE, intense, quick silvery. We’re the people you want to be close to in a crisis, we will get you out. It may be this one allele causing it all.

pic by michelle kwajafa

Of course, the whole of modern society is overcafeinated. We LOVE quick, smart, fast and extravert. So it might be that my inborn tendency (the mutation) was exagareted by the time and society I live in.

I have not had the pin ball machine head for a few years now… Also, the “inner pounding” (roaring, ‘daveren’ in Dutch) has been gone for a while now.
Both since I started progesterone. And Valerian.

(Valerian does something with some neurotransmitters…. need to refind.. GABA, it interacts with GABA. It’s an agonist, a promotor.

“GABA does not penetrate the blood–brain barrier; it is synthesized in the brain. It is synthesized from glutamate using the enzyme L-glutamic acid decarboxylase and pyridoxal phosphate (which is the active form of vitamin B6) as a cofactor. GABA is converted back to glutamate by a metabolic pathway called the GABA shunt. This process converts glutamate, the principal excitatory neurotransmitter, into the principal inhibitory neurotransmitter (GABA).
It gets transformed and it used as fuel for the citric acid cycle”
Need to read up on GABA and glutamate and wether all enzymes for their pathways are good in me.)

Now I’ve lost the plot. But I’m very interested. It ties together the pinball machine, the constant Fight or Flight, the sensitivity, the parasympathethic nervous system and the mutation. Above all: it ties together some particular characteristics I have noticed in me compared to other people. I’ll go to sleep now, talk to you later.
pic by Florin Garoi