interesting and curious frangile post about "adrenal fatigue"

[Jean]

Adrenal fatigue isn’t an actual disease, so this entire discussion is pretty much pointless.

Your CNS doesn’t “burnout” either.

Seriously, life would be a lot simpler if people stopped inventing fantasy illnesses and diagnosing themselves with them on the internet.

There are about 8 billion conditions that cause fatigue or mental impairment of some kind. Cortisol is very rarely to blame, and is in fact an anti-stress hormone. I would imagine sleep deprivation, depression, and hypothyroidism are the most common causes of “adrenal fatigue” hypochondria.

Your adrenal glands can produce ridiculous amounts of catecholamines

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Sometimes what will happen is due to an extended hypodopaminergic state, the GR/MR receptor density in the pituitary gland increases, leading to your brain incorrectly sensing cortisol levels being higher than they are. This is IMO likely an adaptation of efficiency– if the environment isn’t challenging or requiring goal-directed behavior, then lowering catecholamine output slows the metabolism and increases efficiency. The problem with that being that after an extended period of diminished ACTH secretion by the pineal, the adrenal glands atrophy somewhat as another plastic response to increase efficiency, since they aren’t being used much.

Sort of like sitting on your ass and watching your muscles atrophy. But all these adaptations are plastic and reverse with say, cortisone therapy.

QUOTE
those with adrenal fatigue are told to lay off stims, why is that? is it just to prevent further CNS burnout, which results in adrenal fatigue,, or is cortisol really the source of the problem??

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Cortisol does not directly affect the GR/MR density in the pituitary, it is controlled by DA.

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just resting does not help those with adrenal fatigue

It can, sort of …

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In studies on people with CFS, it was found that relatively intense exercise was actually the best treatment, leading to not only the best long-term results but the best reduction in acute symptoms….

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That is why stimulants can lead to adrenal fatigue by first burning out youre CNS.

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Stimulants are a form of stimulation and also cause downregulation.

Not unless you take stupidly high neurotoxic doses they don’t. Dopaminergic stims actually lower the GR/MR density in the pituitary, thus decreasing negative feedback and increasing ACTH responsiveness. stimulants are an extremely effective treatment in the symptoms of atypical depression and PTSD which share this receptor density problem and decreased ACTH secretion issue.

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What are ways that you can avoid CNS burnout while working out everyday and using stims? Im looking for nootropics/supplements.
Is selegiline a good idea? can it lead to CNS burnout as well like other stims?

In moderation no stimulant will cause any symptoms you describe as “burnout” or “adrenal fatigue”. They will with neurotoxic abuse dosages or if they destroy your sleep. That applies to any drug, selegiline, or even depressants like alcohol.

(the exception to this is sudden withdrawal from dopaminergics will lead to a hypodopaminergic state where there is not enough DA to keep the GR/MR receptor density in check)
Right, and that’s because abusing drugs is fucking retarded, as is quitting them cold-turkey. Moderation and balance are key.

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i agree with you here; can anyone explain why? CNS involved?? that answer will solve a lot of problems for me….
too bad im addicted to nicotine now but i find it very different than other stims..hope it doesnt lead me down the same path

Primarily: reversal of sleep deprivation, from deficits in both duration and architecture; changes in baseline mental state that enhance perception of drug’s effects. Also to a lesser extent, reversal of some D3 and B2 receptor downregulation.

Did you know that nicotine disrupts sleep if worn as a patch… but the withdrawal from not wearing the patch, even overnight, disrupts sleep more than the patch does?

Oh, and then we can get into what caffeine does to sleep. My roommate, for example. He drinks caffeinated beverages all day and night, and has an erratic sleep schedule and complains of fatigue. I convinced him to cease caffeine consumption after noon once, and his sleep and fatigue levels improved, but soon he was back to hitting the (soda) bottle again, and is now continuing to suffer the same symptoms while being too indolent and apathetic to even realize it.

Caffeine should be consumed in moderation, only in the morning, and preferably only in tea form, where the tea (perhaps theanine, but ultimately unknown) counteracts many of the later effects that night on sleep architecture.

Nicotine should be worn as a patch 24/7 unless you use it very intermittently (less than once per day), in which case it should be used in gum form.

Amphetamines should be used at a consistent minimally necessary dosage and the dose and timing must be consistent to ensure adaptation to the wakefulness effects. In patients with ADD they actually enhance sleep quality after tolerance is gained (which takes about 1 month at the same dose/timing).

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Maybe use it around bedtime to make sure cortisol is ultra low and promote better sleep? Would that promote better sleep? Or just promote hypoglycemia and an adrenal hormone rebound?

Why? If you have cortisol from stress, cortisol reduces the negative affective mood and decreases some of the excessive inflammation.

The best idea is probably eliminating the stressor but I don’t see why you’d want to lower cortisol levels. It’s a symptom, not a cause… and it even helps attenuate the cause.

Cortisol often enhances sleep, consider rheumatism and latitude/season; decreased light -> decreased cortisol -> increased pain, joint stiffness, inflammation, worsened sleep, etc. But as the light increases in summer, and cortisol levels increase during sleep, sleep quality improves as does the very physical condition of the body itself.

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[billy3z]

hmmm… I really wonder why then after years of progressing unexplained fatigue that I suddenly started developing/experiencing hypoglycemic episodes more and more even though I am not diabetic…. Then amazingly when I started supplementing with Hydorocortisone my hypoglycemic bouts stopped even though fatigue still continues….

[DrMariano2]

Hypoglycemia is not diabetes. Hypoglycemia may occur in diabetes when a person has large a dose of insulin.

Hydrocortisone has many effects. Some include: increasing insulin resistance (which can raise blood sugar), helping reduce norepinephrine signaling (which can reduce energy under certain circumstances, where norepinephrine signaling is necessary for energy production), and reduce inflammatory cytokine signaling (which can result in a restoration of liver blood sugar production, and an improvement in energy).

However, there are numerous signaling and metabolic pathways that determine energy production. Thus, hydrocortisone may not always improve energy when there are other problems in the system.

And when adding hydrocortisone causes an imbalance in the system that is sufficient, problems instead may occur. Thus, its systemic effects need to be considered when assessing treatment.

[wondering]

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[Jean]

I think I made a fundamental mistake in my approach to heal my “adrenal fatigue”.

After many years on hydrocortisone ( 30 mg) I’ve decided for myself to stop HC. My approach with my physician was lowering the inflammation and taking small doses of stimulant for my ADD. The result is amazing because for the first time i can stop HC for 2 months with success.

Unfortunately recently I had a crash. (exhausted, brain fog, pain increases (especially quadriceps and low back), zombie effect and sometimes even nausea after a hard intensity training

I tried to understand the crash and I realized that the crash arrive because I stop abruptly stimulant for few days. I fact I’ve learning in the past that It’s not so good to take everyday low dose of stimulant because you can increase “adrenal fatigue” or make adrenal worse.

Recently, I made an incredible experience, I had a crash again, and I took the stimulant despite high exhaustion …. I feel well again. I think the way of this frangible post who explain that HC is not necessary but for him SSRIs, SJW, stimulants, and antioxidant/anti-inflammatories (e.g. curcumin) pretty much constitute the arsenal. In fact, it’s for myself a good way to improve HPA axis.

I’m interested to understand that sometimes what will happen is due to an extended hypodopaminergic state, the GR/MR receptor density in the pituitary gland increases, leading to your brain incorrectly sensing cortisol levels being higher than they are

I speak about that to my physician and this is a new area of promising research

[DrMariano2]

You have a interesting point.

In attention deficit/hyperactivity disorder, there is suboptimal dopamine signaling.

You may call this a “hypodopaminergic state” but in some cases, this is not necessarily so.

For example, there is the case of dopamine resistance causing ADHD. By dopamine resistance, I mean there may be a genetic mutation in the dopamine receptor such that binding to dopamine is impaired. Thus a higher dopamine concentration is necessary to increase receptor binding in order to provider adequate activation of dopamine receptors. In these patients, dopamine levels are markedly elevated.

—

When a person with attention deficit/hyperactivity disorder also has adrenal dysregulation, it may be necessary to maintain stimulant treatment to maintain nervous system dopamine signaling despite the risk of excess norepinephrine signaling (from stimulant treatment) causing adrenal dysregulation.

In such a case, one has to compensate for the excess norepinephrine signaling through other measures such as treatment with hydrocortisone or other alternative to help prevent adrenal dysregulation.

The presence of both conditions requires simultaneous treatment. When ADHD is a co-morbid condition, maintenance of stimulant treatment, not withdrawal of stimulant treatment may be necessary and needs to be compensated for if stimulant treatment also worsens adrenal dysregulation.

—

Some of my patients in this conflict-filled situation can be very difficult to keep stable, particularly when stimulant dose is high. For example, I had to use a 54 mg dose of Concerta – when I usually use an 18 mg dose – in a young adult patient, who had ADHD and a serious Bipolar Disorder, I had to use numerous mood stabilizing medications just to keep him stable. Without high stimulant treatment, mood would be stable but he would also be seriously disabled – unable to function in school or a work situation or in activities or daily living.

—

Note that the underlying causes for adrenal dysregulation still need to be found (as much as possible) so that they can be directly addressed – if there are other possible causes, not just stimulant treatment. Hydrocortisone is primarily a supportive treatment since it may not address the cause of adrenal dysregulation – unless a person has primary adrenal insufficiency.

[Jean]

@DrMariano 3212 wrote:

You have a interesting point.

In attention deficit/hyperactivity disorder, there is suboptimal dopamine signaling.

You may call this a “hypodopaminergic state” but in some cases, this is not necessarily so.

For example, there is the case of dopamine resistance causing ADHD. By dopamine resistance, I mean there may be a genetic mutation in the dopamine receptor such that binding to dopamine is impaired. Thus a higher dopamine concentration is necessary to increase receptor binding in order to provider adequate activation of dopamine receptors. In these patients, dopamine levels are markedly elevated.

—

When a person with attention deficit/hyperactivity disorder also has adrenal dysregulation, it may be necessary to maintain stimulant treatment to maintain nervous system dopamine signaling despite the risk of excess norepinephrine signaling (from stimulant treatment) causing adrenal dysregulation.

In such a case, one has to compensate for the excess norepinephrine signaling through other measures such as treatment with hydrocortisone or other alternative to help prevent adrenal dysregulation.

The presence of both conditions requires simultaneous treatment. When ADHD is a co-morbid condition, maintenance of stimulant treatment, not withdrawal of stimulant treatment may be necessary and needs to be compensated for if stimulant treatment also worsens adrenal dysregulation.

—

Some of my patients in this conflict-filled situation can be very difficult to keep stable, particularly when stimulant dose is high. For example, if I was forced to use a 54 mg dose of Concerta – when I usually use an 18 mg dose – in a young adult patient, who had ADHD and a serious Bipolar Disorder, I had to use numerous mood stabilizing medications just to keep him stable. Without high stimulant treatment, mood would be stable but he would also be seriously disabled – unable to function in school or a work situation or in activities or daily living.

—

Note that the underlying causes for adrenal dysregulation still need to be found (as much as possible) so that they can be directly addressed – if there are other possible causes, not just stimulant treatment. Hydrocortisone is primarily a supportive treatment since it may not address the cause of adrenal dysregulation – unless a person has primary adrenal insufficiency.

OK thank you, It’s very fascinating and interesting.

[Jean]

@DrMariano 3212 wrote:

You have a interesting point.

In attention deficit/hyperactivity disorder, there is suboptimal dopamine signaling.

You may call this a “hypodopaminergic state” but in some cases, this is not necessarily so.

For example, there is the case of dopamine resistance causing ADHD. By dopamine resistance, I mean there may be a genetic mutation in the dopamine receptor such that binding to dopamine is impaired. Thus a higher dopamine concentration is necessary to increase receptor binding in order to provider adequate activation of dopamine receptors. In these patients, dopamine levels are markedly elevated.

—

When a person with attention deficit/hyperactivity disorder also has adrenal dysregulation, it may be necessary to maintain stimulant treatment to maintain nervous system dopamine signaling despite the risk of excess norepinephrine signaling (from stimulant treatment) causing adrenal dysregulation.

In such a case, one has to compensate for the excess norepinephrine signaling through other measures such as treatment with hydrocortisone or other alternative to help prevent adrenal dysregulation.

The presence of both conditions requires simultaneous treatment. When ADHD is a co-morbid condition, maintenance of stimulant treatment, not withdrawal of stimulant treatment may be necessary and needs to be compensated for if stimulant treatment also worsens adrenal dysregulation.

—

Some of my patients in this conflict-filled situation can be very difficult to keep stable, particularly when stimulant dose is high. For example, I had to use a 54 mg dose of Concerta – when I usually use an 18 mg dose – in a young adult patient, who had ADHD and a serious Bipolar Disorder, I had to use numerous mood stabilizing medications just to keep him stable. Without high stimulant treatment, mood would be stable but he would also be seriously disabled – unable to function in school or a work situation or in activities or daily living.

—

Note that the underlying causes for adrenal dysregulation still need to be found (as much as possible) so that they can be directly addressed – if there are other possible causes, not just stimulant treatment. Hydrocortisone is primarily a supportive treatment since it may not address the cause of adrenal dysregulation – unless a person has primary adrenal insufficiency.

@Jean 3220 wrote:

OK thank you, It’s very fascinating and interesting.

I agree that you say : “Hydrocortisone is primarily a supportive treatment, but adrenal dysregulation still need to be found (as much as possible) so that they can be directly addressed”t
Below This a post of Dubio, he think that HC mpairs the plasticity of the HPA, also reduces the endogenous HPA response to stress and is unable to mount an appropriate HPA response to amphetamine administration. Do you agree with that ?

Amphetamine simulates (and acts as) a stressor on the body, primarily by stimulating catecholamine release. This is manifested, at least in part, by an increase in HPA activation which is partly responsible for the drug’s therapeutic effects.

One of the reasons I’m not a big fan of HC supplementation (particularly long-term) is that it impairs the plasticity of the HPA. It’s been well-documented that exogenous HC not only reduces endogenous production, but also reduces the endogenous HPA response to stress. What is likely occurring in your case is that your body is unable to mount an appropriate HPA response to amphetamine administration, and as such, you’re experiencing depression and fatigue when you take it. I’ve noticed this before when taking amphetamine under symptoms of low cortisol.

There’s essentially no evidence that exogenous HC is valuable in treating any sort of disorder, and it may actually do harm. So my advice would be to taper off the HC, and then try amphetamine again after the taper. Be aware than an SSRI or buspirone may help make an HC taper less uncomfortable. If you’re dead-set on taking HC, though — and I really don’t recommend it — you need to take a bit extra every time you dose amphetamine.

I suspect this is more closely related to HPA disturbance combined with amphetamine withdrawal than any kind of depletion. The bizarre sensation is just reduced DA tone consequent to withdrawal.

[DrMariano2]

@Jean 3222 wrote:

I agree that you say : “Hydrocortisone is primarily a supportive treatment, but adrenal dysregulation still need to be found (as much as possible) so that they can be directly addressed”

This a post of Dubio, he think that HC mpairs the plasticity of the HPA, also reduces the endogenous HPA response to stress and is unable to mount an appropriate HPA response to amphetamine administration. Do you agree with that ?

Amphetamine simulates (and acts as) a stressor on the body, primarily by stimulating catecholamine release. This is manifested, at least in part, by an increase in HPA activation which is partly responsible for the drug’s therapeutic effects.

One of the reasons I’m not a big fan of HC supplementation (particularly long-term) is that it impairs the plasticity of the HPA. It’s been well-documented that exogenous HC not only reduces endogenous production, but also reduces the endogenous HPA response to stress. What is likely occurring in your case is that your body is unable to mount an appropriate HPA response to amphetamine administration, and as such, you’re experiencing depression and fatigue when you take it. I’ve noticed this before when taking amphetamine under symptoms of low cortisol.

There’s essentially no evidence that exogenous HC is valuable in treating any sort of disorder, and it may actually do harm. So my advice would be to taper off the HC, and then try amphetamine again after the taper. Be aware than an SSRI or buspirone may help make an HC taper less uncomfortable. If you’re dead-set on taking HC, though — and I really don’t recommend it — you need to take a bit extra every time you dose amphetamine.

I suspect this is more closely related to HPA disturbance combined with amphetamine withdrawal than any kind of depletion. The bizarre sensation is just reduced DA tone consequent to withdrawal.

Whether or not Hydrocortisone impairs the endogenous HPA response to stress depends on the dose and the particular person’s condition.

For example, in post-traumatic stress disorder, there is significant adrenal dysregulation. Often cortisol is below 5.0 ug/dL (137.95 nmol/L). There is evidence that sub-physiologic replacement doses of hydrocortisone is useful in improving function – including improving HPA Axis function – in posttraumatic stress disorder. And, improving the person’s capacity to respond to stress.

When adding exogenous hydrocortisone, there is going to be some suppression of adrenal cortex output of multiple hormones (such as progesterone, DHEA, testosterone, estradiol, and endogenous cortisol). Whether or not the decrease in the other hormones is significant in impairing function depends on the person. Some patients have difficulty handling the decrease in other hormones. This is why I would call the use of hydrocortisone alone an incomplete treatment since one has to consider also replacing the other hormones to make up for the deficit. Some patients, however, can do well despite the decrease in the levels of the other hormones. Other signaling systems, in these patients, are able to compensate.

If, suppression of adrenal function is such that adrenal output of cortisol in response to stress is insufficient to match central nervous system norepinephrine signaling, then one has adrenal dysregulation – and an impaired HPA response to stress. Adding cortisol, in this case, would help support the HPA response to stress – so long as the patient can tolerate the decrease in other adrenal hormones. In this case, treatment with hydrocortisone (cortisol) would be helpful. This is why many people can benefit form hydrocortisone treatment.

—

In some patients with ADHD, who have no pre-existing adrenal dysregulation, amphetamines at high enough doses, can pose a stress which can lead to adrenal dysregulation. Since there is no pre-existing adrenal dysregulation, then one way to recover from adrenal dysregulation is to stop amphetamine treatment to allow the system to recover from stress. This is called a drug holiday. Some children, for example, only use stimulant treatment on weekdays – when they have to do schoolwork. And they don’t use stimulants on the weekends – when they don’t have to do school work.

However, if amphetamine use is necessary to treat ADHD such that stopping treatment causes significant disability, then treating the resulting adrenal dysregulation becomes necessary to maintain function. Otherwise, the person may become dysfunctional because of the resulting adrenal dysregulation. Manifestions include loss of energy, loss of motivation, irritability, anger outbursts, depression, etc.

—

Many patients with ADHD, however, already have pre-existing adrenal dysregulation. In such patients, it is important to address the adrenal dysregulation since the existence of it may make stimulant treatment intolerable. Stimulant treatment may worsen the pre-existing adrenal dysregulation. Obviously, in this case, adrenal dysregulation is caused by other factors, not by stimulant treatment. And it is important to search for other causes.

—

Exogenous hydrocortisone, of course, is valuable for treating adrenal insufficiency (Addison’s Disease), asthma, rheumatoid arthritis, various skin disorders, and other inflammatory diseases.

—

It is preferable to try and find the causes and treat the causes of adrenal dysregulation (the non-adrenal causes of adrenal dysregulation).

Sometimes, however, the cause cannot be yet found or the cause is incurable (e.g. some chronic active viral illnesses, autoimmune illness). In these cases, chronic and intractable suppression of adrenal function may be present. And the chronic use of hydrocortisone (with or without additional adrenal cortex hormones) would be an option to support the signaling actions of the adrenal gland in response to stress.

—

I, myself, don’t use hydrocortisone that often since if I can find and address the causes of adrenal dysregulation, treatment with hydrocortisone isn’t needed.

Most of my patients have conditions that have chronic underlying causes of adrenal dysregulation that are so strong or extreme, they overwhelm what subphysiologic replacement doses of hydrocortisone can do. As such, sub-physiologic doses of hydrocortisone is a weak and often ineffective treatment in these patients. Searching for and addressing the causes of adrenal dysregulation is the preferred solution.

I generally would not use supraphysiologic doses of hydrocortisone unless a person has an illness that requires such a dose (e.g. intractable migraine unresponsive to conventional treatment – where hydrocortisone is used in a quick 5-day course, adrenal insufficiency when the person is under significant stress).

—

If using hydrocortisone in treatment, one has to consider options to addressing possible adverse effects by either dose adjustment or the addition of compensatory treatments. This includes the possibility of osteoporosis, insulin resistance, weight gain, acid-reflux disease or gastric ulcers, etc.

[Jean]

Thank you Dr Mariano.
It’s more clear now for me.:)

[Jean]

@Jean 3224 wrote:

Thank you Dr Mariano.
It’s more clear now for me.:)

Another point that interesting is hypersensitive DA autoreceptor that block the DA release. I’m not sure that a CFS or ADD problem.

Stimulants
by Jay A. Goldstein, M.D.

When I began to treat patients with CFS, I was amazed to see many of them fall asleep after taking dextroamphetamine (Dexerdrine) and similar agents such as methylphenidate (Ritalin), phentermine (Ionamin), and pemoline (Cylert). Later, when amphetamine salts (Adderall) were introduced, the same paradoxical response often occurred. The cause of this sedation is central to the etiology of neurosomatic disorders (my term for inappropriate handling of sensory and cognitive input by the brain).

The “nucleus accumbuas” (NAc) is a part of the brain involved with reward, particularly expectation of reward. It has a core and a shell, like a tiny avocado, the shell is germane to the present discussion. Its primary neurotransmitter is dopamine (DA), although others, particularly norepriephrine (NE) and glutamate are also involved. For reasons too complicated to explain here (they’ll be in my next book), either not enough DA is available in the NAc or the receptors for it are not sensitive enough (“downregulated”).

Decreased DA in the NAc has profound effects upon how an individual feels and thinks and how the parts of the brain with which it communicates function. Many, perhaps most, of CFS and FMS (neurosomatic) symptoms are related to DA and NE. Fatigue, pain and attentional problems are common consequences.

Somnolence after taking stimulants is analogous to relapse after ejaculation. Both are due to absolute or functional DA and NE deficiency and could not be easily explained by receptor downregulation. Stimulants enhance secretion of these neurotransmitters. If the levels of the these substances are too low in the secreting (“presynaptic”) neuron to begin with, squeezing out a little bit more may result in marked worsening of symptoms subsequently.

It pains me to write this, but the situation is more complicated than I have just described. Presynaptic DA may be totally depleted, or the mechanism by which stored DA moves to the edge of the presynaptic membrane where it is secreted (the “ready releasable pool”) may be dysfunctional.

Neither of these explanations can account for the rapid symptom fluctuations commonly seen in neurosomatic disorders, and certainly could not demonstrate why increasing DA transmitters can cause a relapse. These phenomena can be interpreted, however, as stemming from hypersensitivity of the DA autoreceptor.

What is an autoreceptor? The presynaptic neuron, which secrets most transmitters, must have a mechanism to sense how much transmitter it has secreted, (i.e., how much is in the synapse). How autorecptors themselves are regulated is imperfectly understood, but calcium ions are thought to be involved. Calcium is perhaps the most important intracellular regulating element.

If the DA autoreceptor is hypersensitive, small amounts of secreted DA will result in a marked decrease of further DA secretion. Such a scenario may be applicable to patients with neurosomatic disorders. An ideal drug, therefore, would block the DA autoreceptor and “fool” the neuron so that a low DA concentration is sensed in the surrounding environment. Researchers have been trying to develop a drug that blocks the DA autoreceptors without affecting similar receptors postsynaptically since the 1979’s. It has recently been reported that Arvid Carlsson, who shared the Nobel Prize in Physiology of Medicine in 2000, has developed such an agent, currently name OSY6162, and is testing it on human patients. Its most obvious use would be in Parkinson disease, which is similar to neurosomatic disorders in certain ways. Increasing DA in the NAc shell, which is difficult to do without using drugs of possible abuse, should be facilitated by a DA autoreceptor antagonist.

[Jean]

eatree, on 29 August 2010 – 03:48 AM, said:
This is a great post of Dr Mariano who explain the utility of hydrocortisone for many problems. I agree with him that you need sometime in some state HC.
I respect the view too of ExDubio who explain that HC is not necessary but for him SSRIs, SJW, stimulants, and antioxidant/anti-inflammatories (e.g. curcumin) pretty much constitute the arsenal.

I’m not sure we disagree entirely. I’d like to clarify that I have the utmost respect for Dr. Mariano. While I’m just an internet “pundit” of sorts, he’s actually practicing the kind of medicine that the rest of the medical community ignores. He’s a phenomenal doctor — maybe the best in the US — and while I think he tends to step out on speculative territory at times, his willingness to see the results of a given therapy through and provide an alternative route in case of failure makes him the cutting edge doctor he is.

Now why do I look down on HC therapy? Mostly because I — and many others on this board — have failed to find lasting, positive results in HC treatment. It’s not just us, either; the three of four studies that came out a few years ago trying HC in CFS/fibromyalgia found very weak evidence of improvement; and, in fact, the one study that did register improvement also noted nontrivial HPA shutdown.

The problem is that HPA abnormalities in these conditions are likely secondary to immunological or neurochemical aberrations. Even if the HPA aberration is primary, it also seems that the complex interplay between the monoamines, cytokines, and the HPA prevent HPA-targeted therapies from showing long-term promise.

Does this mean HC never works? Certainly not. Dr. Mariano would not prescribe something that had never worked, and HC would not be such a commonly discussed topic were it worthless. But I tend to think its efficacy is largely overstated. I’m not sure how old the mentioned post of Dr. Mariano’s is, but recently even he has moved more toward immunological modulation and away from direct HC supplementation, at least in a large nubmer of his patients.

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And an important reason to try to identify and address these other problems is that too often, in my experience, when these other problems are not directly addressed, hydrocortisone does not work well. For example, in severe mental illness, despite severe adrenal dysregulation, hydrocortisone may not work well at all despite having very low cortisol levels.

—

That is not to say that hydrocortisone does not work well all the time. It helps many patients. Again, however, it is important to identify and address the underlying problems.

Even here, Dr. Mariano is getting at similar points to the ones I’ve made in the past. HC therapy works sometimes, but not always. And it doesn’t seem to be entirely consistent.

At any rate, I’m not sure the views are as different as you think. I think the relevant point here is that HC does not seem to be entirely fixing your problems, only temporarily reducing some of your symptoms. This is not a real treatment, in my opinion.

adrenoguy, on 30 August 2010 – 01:22 PM, said:
The interesting part is this:

Is this something we have to be concerned about?

I’m going to quote myself (forgive me) from the Corticosteroid Receptor and HPA post:

Quote
Acutely, alpha1 agonism increases HPA output and beta agonism decreases HPA output. Moreover, alpha1 agonism also directly (as opposed to indirectly, through changes in CORT) reduces MR/GR receptor expression and beta agonism increases MR/GR receptor expression in the hippocampus. In a very real sense, beta agonism in the CNS acts as a “brake” to the HPA, whereas alpha1 agonism has a strong, activating influence.

The peculiar part is that chronic alpha1 antagonism, through alpha/beta interaction, actually leads to beta receptor downregulation and a consequent increase in HPA activity by (in adrenalectomized rats) increasing MR expression or (in healthy rats) increasing CORT response to stress. This may have therapeutic implications; in particular, these mechanisms suggest a means by which chronic adrenergic stimulation of alpha1 adrenoceptors could sensitize beta adrenoceptors and result in HPA hypoactivity.

NE is a tricky and confusing chemical. To add to the picture, we know (IIRC) that alpha1 is more or less maximally activated in the HPA at baseline. So, in terms of acute effects, extra NE output is going to activate beta adrenergic receptors and reduce HPA output. Of course, this is complicated by the fact that NE has stimulatory roles on DA and 5-HT, both of which have stimulatory roles on the HPA (more or less).

The bigger issue is, however, that chronic alpha1 agonism seems to result in central beta receptor upregulation, which has a inhibitory tone on HPA activity by increasing MR expression, which lowers the basal HPA setpoint, and likely exacerbates inflammatory conditions.

What makes this more confusing, however, is that because NEergic stimulants have excitatory influences on other neurotransmitter systems, their effect on the HPA may not be apparent until either (a) the stimulant is discontinued or ( a major life event (or stressful event) causes disruption of normal monoamine balance, and reduced HPA drive then results in a greater influence of MR receptors, and bam — you end up with what might be called “adrenal shutdown”. (Which, of course, has nothing to do with the adrenals.)

This is all a bit speculative, but I think this is what Dr. Mariano has noted.

So in other words, pseudoephedrine (without other drugs), epehedrine, and pure NEergics may not be great for long-term use. However, quoting myself again:

Quote
Though D2 receptors do not seem to substantially modulate the HPA axis, D1 agonism reduces GR receptor affinity in the ventral striatum (which may serve to disinhibit CRH neurons) and also reduces MR affinity in the hippocampus (which also serves to disinhibit CRH neurons), thus producing a net stimulatory effect on the HPA.

Add this in, and the story comes full circle. D2 agonists don’t fix any problems that are HPA-related, and we already know that. But why do amphetamine and combinations like deprenyl+pseudoephedrine (ATB!) seem to work? Because, I imagine, the increased D1 tone results in an attenuation of the negative effects of NE on the HPA.

For what it’s worth, if amphetamine and/or deprenyl are not options, alpha-2 agonists and/or alpha-1 antagonists may be able to accomplish similar results, though perhaps with greater side effects.

And this also answers perhaps another mystery; why does deprenyl seem to induce “adrenal fatigue” symptoms, when amphetamine and deprenyl+pseudoephedrine do not? Probably because, though it decreases MR/GR tone in the hippocampus and ventral striatum, deprenyl also reduces NEergic tone in the hypothalamus (IIRC), and this may actually antagonize the tonic maximal alpha1 stimulation of HPA activity.

[Author]

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