How to lower norepinephrine

[dbkita]

dbitka...y would you not do a spinal tap apart from the fact that it is invasive and painful?

Because my brother had one for another reason and there was a complication and he developed viral meningitis and almost died from it (at which point they had to do btw additional spinal taps).

 

[invisiblejungle]

For those of you who are interested in the connection between norepinephrine and adrenal dysfunction:

http://www.definitivemind.com/forums/showthread.php?t=560

To summarize some issues a lot (since the actual mechanisms can be mind-bogglingly complex):

Chronic or traumatic stress may lead to hypothalamic-pituitary-adrenal axis dysregulation (the term which I believe is more accurate to use than the term "adrenal fatigue"), HPA dysregulation for short.

HPA dysregulation leads to lower production of adrenal cortex signals/hormones. This includes lower cortisol and/or DHEA, progesterone, pregnenolone, testosterone, estradiol, or aldosterone.

The primary signal for stress is norepinephrine. Norepinephrine is in a positive feedback loop with corticotropin releasing hormone. This positive feedback loop is interrupted by cortisol signaling. To increase norepinephrine, the brain has to also reduce production of some or all of the control signals that suppress norepinephrine signaling. These include reductions in serotonin, dopamine, GABA, etc.

Stress (particularly if it is a perceived threat), may lead to an increase in pro-inflammatory cytokine signaling from the brain and from the immune system (which is directly innervated by neurons of the sympathetic nervous system - the primary norepinephrine-releasing neurons of the nervous system). Stress may also lead to an increase in histamine signaling from brain mast cells. These changes lead to an activation of the immune system. These changes in large excesses may lead to an increase in inflammatory processes. The loss of anti-inflammatory signaling - which includes cortisol, DHEA, progesterone and testosterone - exacerbates these pro-inflammatory changes.

Excessive pro-inflammatory cytokine signaling may trigger automatic defensive programs in the brain. Defensive programs may induce behavioral changes including depressed mood, loss of interest or motivation in activities, loss of enjoyment from activities, social isolation, changes in sleep including the desire to sleep excessively.

There may be a loss of energy from excessive pro-inflammatory cytokine signaling. The actual mechanisms of the loss of energy are not clear. I currently speculate that perhaps there may be impaired brain astrocyte conversion of thyroxine (T4) to triiodothyronine (T3) - which leads to a hypothyroid central nervous system with a euthyroid body (as in Alzheimer's disease). Perhaps the increase in pro-inflammatory cytokines is one of the signaling problems leading to HPA dysregulation, aside from excessive norepinephrine signaling. However, other regulatory systems may also be involved - such as the opiate signaling systems (which also involve dopamine signaling).

HPA dysregulation, from whatever cause, leads to a loss of energy. The loss of energy production, however, under some circumstances. These circumstances include bipolar disorder and attention deficit/hyperactivity disorder with hyperactivity. In these cases, norepinephrine production is an effective signal for energy.

Nutrition plays a large role in the development of HPA dysregulation. Omega 3 vs. Omega 6 balance helps determine the balance between inflammation and anti-inflammation. Various nutrients (such as the B-vitamins, fat soluble vitamins, magnesium, etc) are cofactors for many of the processes involving signal production. Vitamin A and D are generally anti-inflammatory signals. Vitamin D reduces insulin resistance (which helps the body tolerate low blood sugar from impaired cortisol signaling), increases serotonin and dopamine production. Vitamin A helps regulate the sensitivity to various hormones/signals such as thyroid hormone.

The other endocrine signaling systems such as the reproductive system are in play. Testosterone helps reduce norepinephrine, increases dopamine production. It also suppresses adrenocorticotropin releasing hormone and directly inhibits adrenal cortex activity - this may be significant depending on the sum of signaling interactions and problems a person has. Estrogen acts similarly to a monoamine oxidase inhibitor - thus increasing serotonin, norepinephrine and dopamine (but serotonin primarily). Estrogen in relative excess may be pro-inflammatory, reduces free thyroid hormone. Thyroid hormone signaling loss is compensated by an increase in norepinephrine production with simultaneous activation of adrenal cortex signals. Over time, however, this compensation may fail as HPA dysregulation occurs. Insulin, glucagon, the incretins, etc. also have a role. Insulin, itself, is pro-inflammatory. Growth hormone has a calming effect and is anti-inflammatory. Etc. etc. etc. etc.

The entry point of all these processes is stress. This is represented primarily by norepinephrine signaling. However histamine (from brain mast cells) and pro-inflammatory cytokines (from brain microglia) are also involved in the process. Stress induces responses that are ostensibly designed to improve survival. The problem is that in the modern world, these responses may be dysfunctional instead.

===

Given the complexity of the interactions involved, a single intervention may or may not work. Which direction an intervention goes depends on the sum of the changes that occur as a result of that intervention. In psychiatry, the usual answer to a question is "It depends."

Stress is the entry point. Environmental and behavioral interventions would clearly help with few downsides.

Low dose testosterone may help, particularly in women, by helping to reduce norepinephrine and increasing dopamine signaling, and helping to reduce pro-inflammatory signaling. Low dose testosterone would not help in men since it may do nothing or it would suppress endogenous production of testosterone, leading to lower overall testosterone levels. Men would need replacement doses of testosterone. Testosterone, however, may also worsen adrenal cortex function depending on a person's susceptibility to this. In men, exogenous testosterone treatment also suppresses testicular thyroid releasing hormone production, leading to a loss of thyroid hormone production, which then leads to an increase in norepinephrine production. This is why in certain men, even if hypogonadal, testosterone treatment is intolerable. The rest of the system has to be optimized before testosterone treatment can be done.

Tamoxifen (I would prefer this to Clomiphene due to the visual changes that can occur with Clomiphene) is a weak estrogen. This blocks the stronger estrogens from being sensed by the brain. This then causes the brain to release more Luteinizing Hormone to stimulate testosterone production, leading to estrogen production. The increase in testosterone would have the effects listed previously. The problem is that Tamoxifen also blocks estrogen. This leads to lower estrogen signaling activity. Estrogen helps control norepinephrine by increasing serotonin and dopamine production. Estrogen is also needed to improve sensitivity to testosterone by increasing testosterone receptor production. Estrogen is also important in generating energy, motivation, drive, competitiveness, sex drive (libido). Estrogen (particularly in women) is important for neuron growth and memory. The loss of estrogen signaling, depending on the balance with testosterone, may lead to negative effects. If testosterone production is driven high enough, then perhaps this would improve things overall. This is particularly true in men. However, in women, this may not occur and destabilization of the system and dysfunction may occur instead. This is why many women do not like treatment with Tamoxifen or Arimidex for breast cancer.

Cortisol treatment alone may or may not work. Cortisol treatment in sub-replacement doses helps because it helps break the norepinephrine-CRH positive feedback loop. Cortisol also acts in the brain to improve concentration/focus by allowing the brain to ignore emotionally distracting memories or information. Cortisol also is the most important anti-inflammatory signal that reduces immune system activity. Cortisol triggers gluconeogenesis - helping improve blood sugar production. etc. etc. Thus it can be a useful component of treatment. However, Cortisol treatment alone also suppresses adrenal cortex activity. Thus, there is also a loss of pregnenolone, progesterone, DHEA, testosterone, estradiol, aldosterone, etc. If this loss is large enough, then the person may be worse off than without treatment. Since the majority of these other signals are calming, help control norepinephrine, are anti-inflammatory signals, a significant loss may cause the opposite intended effect of cortisol treatment. This is where some people become more tired, get "brain fog", become more anxious, etc. on cortisol monotherapy.

A systematic treatment has to be considered to address the multiple issues that invariably occur, contributing to HPA dysregulation. Single modality treatments may help - particularly in those people who don't have large problems in the rest of their system. But often, in more severe cases, they don't. A systemic approach would then be needed. I would count the person who responds to monotherapy as very fortunate.

 

[adreno]

Dr. Mariano really knows his stuff about HPA axis dysfunction.

 

[adreno]

dbkita

Since we agree that the immune system is the major controller of the ANS and HPA, why can't we simply use anti-inflammatories (AIs) to treat this? Getting the inflammation under control should theoretically calm down the ANS and allow the HPA to recover. Is is because AIs are not potent enough? Do not target the right cytokines? Do not cross the BBB? Do you have any ideas about this? Since the immune system is central to our problems, it would make the most sense to target the treatment there. And yes I know steroids can do the job, but I don't see why AIs can't work?

 

[dbkita]

For InvisibleJungle:

The one thing I would add is that for many chronic stress alone is not the culprit. That can lead to adrenal fatigue but is recoverable. But for some it is the immune system. Think about. What hormone does more to impede the work of the immune system? Answer: cortisol, among of course other hormones like DHEA, the sex hormones, etc. But really ... cortisol.

For example did you know which system is necessary to grow muscle fibers? The immune system. Why do you think that athletes doing weight training take high levels of certain electrolytes and other substances? Answer to prevent the cortisol stress response from exercise. Why was the cortisol secreted with exercise? To dampen inflammation. The athlete intentionally wants to lower reactive cortisol to give more time for muscle fibers to be laid down post exertion. If they supplement nothing the cortisol actual makes them temporarily susceptible to viruses and such. You can read all about it on the muscle building forums. Someone like me on high glucocorticoids to control an autoimmune disease will find it virtually impossible to go into an anabolic state.

Now back on track ...

The immune system if over-active due to infection or autoimmune disease wants you in a low metabolic low energy fatigued state laying in bed so it can do it work. Fine for an acute illness. But not for a chronic problem that last years. The controls for NE are anti-inflammatory generally or positive neurotransmitters like dopamine and serotonin, and of course GABA. NE runs along with inflammation. Why? NE modulo direct fear / stress response is intertwined with immune system activation. So imagine the immune system is throttling the HPA axis to get cortisol down so it can "do its job". But as cortisol drops and the chains come chronically off the NE "beast" then the sympathetic nervous system is activated. Inflammation is increased. There is now a vicious cycle the loser being the adrenals. Eventually ALL hormones from the HPA axis become dysregulated and vanish.

Such was my story when I was at the brink four years ago. The endocrinologist who saved my life did so by putting me on glucocorticoids (note I am NOT advocating them for most people because standard adrenal fatigue is solvable without them in principle). It took two more years to find the cause and then direct further treatment to achieve improved results. I still needed hormone replacement in many other parts of the HPA (and HPT) axis, i.e. testosterone, DHEA, etc. The final big pieces were florinef and cytomel (since otherwise my body converted t4 to reverse T3).

There is a big difference between standard secondary adrenal fatigue and a full out adrenal collapse brought on by immune system +NE chronic hyperactivation. So while stress is often discussed as a source factor, stress from inflammation can be the main player. i.e. changing your sleep, diet and lifestyle habits have little consequence if you have a fire in your kitchen due to say an autoimmune disease or a Lyme's infection or a mercury overload.

I am probably not explaining this very well, but I have learned the hard way that some of the conventional wisdom about adrenal fatigue (a la Wilson et al) misses (for some people) the really big picture. The missing piece I learned after working with my neuroendocrinologist and in subsequent research is the immune system. Many of those who chronically suffer, need to at least differentially diagnose the possibility of immune dysregulation before they assume standard secondary adrenal fatigue. I am very lucky I stumbled after years into a neuroendocrinologist that understood this.

 

[dbkita]

For those of you who are interested in the connection between norepinephrine and adrenal dysfunction:

http://www.definitivemind.com/forums/showthread.php?t=560

HAHAHA.

Guess who is my neuroendocrinologist. Dr Romeo Mariano in Monterey, CA. Sigh such a small world. Took me 10 years to find him. Off the record, he has stated I am not the worst case but the most complicated case he has ever seen. Such is life. He has done wonders for me.

Btw I don't think my earlier post is in conflict with what InvisibleJungle pasted, I simply was trying to stress the nasty variant that can come with immune system overload where the body itself provides the "stress".

 

[adreno]

HAHAHA.

Guess who is my neuroendocrinologist. Dr Romeo Mariano in Monterey, CA. Sigh such a small world. Took me 10 years to find him. Off the record, he has stated I am not the worst case but the most complicated case he has ever seen. Such is life. He has done wonders for me.

LOL. I've known about him for a few years, but didn't know this was your doctor. Yeah, it's a small world. Or there are just very few good doctors around.

 

[dbkita]

dbkita

Since we agree that the immune system is the major controller of the ANS and HPA, why can't we simply use anti-inflammatories (AIs) to treat this? Getting the inflammation under control should theoretically calm down the ANS and allow the HPA to recover. Is is because AIs are not potent enough? Do not target the right cytokines? Do not cross the BBB? Do you have any ideas about this? Since the immune system is central to our problems, it would make the most sense to target the treatment there. And yes I know steroids can do the job, but I don't see why AIs can't work?

You should use AIs to help. In a sense that is what I have been 'preaching'. That is a better regimen imo than trying to directly block NE unless the person is in dire straits and needs immediate intervention.

I would not be in favor of the NSAIDs those will hit COX and really whack your stomach lining. Believe me when I experimented with 2-3 baby aspirin a day on my own on top of my other stuff, it did help. But then it started to carve my gut since aspirin somehow prevents the stomach from healing the damage induced by prednisone. Not good. Quercetin can work but it is a COMT inhibitor and while at first a cyp3a4 inhibitor it later become an inducer which means faster break down of my glucocorticoids (uggh, been there). Things that block. Curcumin is an option. It simply rips my colon apart. No idea why. There are lots of anti-inflammatories. Prostaglandins series 1 and 3 for example. Ironically sea salt is anti-inflammatory. Vitamin D3 is inflammatory in the gut, but its downstream product 25OH is AI and very important. We could take some time I suppose to formulate a list.

Glucocorticoids are not to be used unless working with a doctor to supervise. My brother uses physiological levels of medrol and does great. He is in the best physical shape of his life. But HRT of any type is very tricky and finding doctors who can and will administer it correctly even harder. My mother recovered in her late 60s after many years of issues and electrolyte problems with right support.

Another piece to the puzzle is the gut. Any gut dysbiosis can really mess up inflammation. I would not be surprised that a large section of people on these forums would see substantial gain just with healing relevant gut dysbioses. So much of your immune system is in your gut.

Also better Krebs cycle activity means less NE, means less inflammatory signaling and so on. Low energy, bad methylation, etc. are terrible stresses on the body. Just like anemia, infections, toxic overload, etc.

The question is how much AI control do you need, does it need to be 24 hour, how does it affect the HPA axis and steroidgenesis, can you bootstrap yourself later on, etc? These are all important questions.

 

[dbkita]

LOL. I've known about him for a few years, but didn't know this was your doctor. Yeah, it's a small world. Or there are just very few good doctors around.

My brother is the one who went to see him first. Took me five more years to make it to him only because I was stubborn. Very bad decision on my part. What was special in his case is when I was on the brink (don't want to relive those memories) he was suitably aggressive in taking action. Still it took two more years to get the right diagnosis. Then things really started to change. So yeah guess who I was referring to about wanting me on Florinef well before I started taking it? Not only due to my labs and symptoms but because it hugely helped my brother with his dysautonomia. Shared genetics

 

[invisiblejungle]

HAHAHA.

Guess who is my neuroendocrinologist. Dr Romeo Mariano in Monterey, CA. Sigh such a small world. Took me 10 years to find him. Off the record, he has stated I am not the worst case but the most complicated case he has ever seen. Such is life. He has done wonders for me.

Btw I don't think my earlier post is in conflict with what InvisibleJungle pasted, I simply was trying to stress the nasty variant that can come with immune system overload where the body itself provides the "stress".

Oh man... When I first read some of your posts, I actually had a feeling that you were seeing him because you use a lot of the same language that he uses. I stayed in Carmel when I flew out there. The beaches here in Chicago simply don't compare...

Mariano was the first one to describe how excessive norepinephrine could be causing my symptoms. I tried various meds, including guanfacine and escitalopram, but nothing had the desired effect. The one thing that he wanted me to try that I didn't want to at the time was T4. My free T3 and free T4 were good, but my total T4 was on the low end of the range. He thought that the sub-optimal total T4 could be the main culprit, but I just wasn't sold because my free's were in a good place. Yeah, I probably should've just tried it. I had nothing to lose...

I actually ordered some Synthroid a couple weeks ago, so we'll see if he was right. If it turns out that I spent all that time spinning my wheels... Oh well, at least I've learned a lot.

 

[heapsreal]

Does dr mariano also directly treat cfs/me with infection/immune type treatments like antivirals and immune mods or just sticks to hormones and neurotransmitter balancing??

 

[dbkita]

Oh man... When I first read some of your posts, I actually had a feeling that you were seeing him because you use a lot of the same language that he uses. I stayed in Carmel when I flew out there. The beaches here in Chicago simply don't compare...

Mariano was the first one to describe how excessive norepinephrine could be causing my symptoms. I tried various meds, including guanfacine and escitalopram, but nothing had the desired effect. The one thing that he wanted me to try that I didn't want to at the time was T4. My free T3 and free T4 were good, but my total T4 was on the low end of the range. He thought that the sub-optimal total T4 could be the main culprit, but I just wasn't sold because my free's were in a good place. Yeah, I probably should've just tried it. I had nothing to lose...

I actually ordered some Synthroid a couple weeks ago, so we'll see if he was right. If it turns out that I spent all that time spinning my wheels... Oh well, at least I've learned a lot.

Yeah guanfacine and clonidine did not work out for me for several reasons. But in hindsight the reason was obvious. My autoimmune disease was not going to get better by simply treating with NE antagonists. For some of us, there is no substitute for corticoid control.

 

[Lotus97]

This might seem like a dumb question, but I've read that taking SAMe increases norepinephrine. If we produce SAMe through methylation does that have the same effect?

 

[adreno]

This might seem like a dumb question, but I've read that taking SAMe increases norepinephrine. If we produce SAMe through methylation does that have the same effect?

Methylation in general will do this. But it will also increase other neurotransmitters, such as 5-HT. Remember it's all about balance, there are no good or bad NTs. Both under- and overmethylation can be a problem in this regard.

 

[Emootje]

Superoxide scavengers in the brainstem may also lower norepinephrine.
O2− reacts with and inactivates NO and thereby modulates its bioavailability.
Low NO bioavailability suppresses NO-mediated GABAergic inhibition in the RVLM (pressor center).
O2−↑ > NO↓ > GABA↓> SNS↑



https://www.jstage.jst.go.jp/article/circj/76/12/76_CJ-12-0399/_pdf

 

[Lotus97]

Methylation in general will do this. But it will also increase other neurotransmitters, such as 5-HT. Remember it's all about balance, there are no good or bad NTs. Both under- and overmethylation can be a problem in this regard.

I definitely get a mood boost from taking B12 sometimes, but it also makes me very wired and/or overstimulated sometimes. I didn't realize methylation itself affected neurotransmitters though.

 

[dbkita]

I definitely get a mood boost from taking B12 sometimes, but it also makes me very wired and/or overstimulated sometimes. I didn't realize methylation itself affected neurotransmitters though.

Methylation is both the gateway to the production and the catabolism of many neurotransmitters. Certainly serotonin and the catecholamines. Remember though it must seem like I rail against NE, you need some NE to function and feel good, else you would just be depressed.

The problem is when it gets out of balance and hyperstimulates the SNS. You don't want sympathetic nervous overload. That is a beast of an issue and very destructive if chronic. NE also factors into the immune system and inflammation. Heck I just saw my neuroendocrinologist today and he was reminding me that my pain increase when I increase certain supplements if from increased inflammation tied into higher NE. Sigh.

 

[Asklipia]

Has anyone used TRH to regulate the immune system?

 

[adreno]

Has anyone used TRH to regulate the immune system?

How would we do that?

 

[invisiblejungle]

Has anyone used TRH to regulate the immune system?

I know TRH can be purchased, but do you think it would have any substantial benefits compared to taking thyroid hormone?

http://www.antiaging-systems.com/209-trh-thyrotropin-releasing-hormone-weightloss