13 replies to this topic

[Heisenburger]

Somebody was mentioning just a few days ago how nice it would be if we could find a substance that normalizes HPA axis function. I think it may have been in the ashwagandha thread, but I have been searching for over half an hour and can’t seem to find it. Last night I stumbled across this paper describing tianeptine’s effects on HPA axis function in stressed rats. Xanax and clonazepam also specifically target the HPA axis (unlike other benzodiazepines) which I believe is why these two benzos are recommended above all others for the treatment of stage fright.

 

What other substances are known to mediate HPA axis kindling?

[OneScrewLoose]

Such a complicated part of our body/mind.

You know, at one point my insomnia was so bad, that I was on two anti psychotics (one being 10mg of Zyprexa) in order to just get to sleep. This only worked 50% of the time and made it nearly impossible for me to wake up in the morning. I then started taking clonidine for something else, and after 10+ prescriptions 15+ supplements, I finally found something that knocked me out 98% of the time, even if I tried to stay up. Sometimes I would be on the computer, on the couch, and just uncontrollably falling asleep. That NEVER happened to me before.

It also finally made me gain weight, after struggling and struggling to do so for 10 years. I would get as low as 130lbs at 5'11". I remember once losing 4 pounds in 4 days because of a lack of calories. And please, please don't fucking call this a golden problem, it's very different as a guy and no one treats you like a man at that wieght. Forget about being attractive to girls either. I was so self-conscious about it, that despite being 180lbs right now, I still have body dysmorphic disorder and see an image of myself at 145lbs, and can not even tell when I gain or lose weight until I step on a scale.

I could not, for the life of me, understand how Clonidine could possibly make me gain weight. I understood that it reduced norepinephrine levels and that's probably what put me to sleep, but I thought the weight thing was just coincidence or placebo. Then I found this study, which put it all together:

http://www.ncbi.nlm....les/PMC3035660/

You see, the orexin neurons in the lateral hypothalamus display alpha 2 receptors only in times of sleep deprivation, otherwise they are hidden. Activation of these receptors by Clonidine shuts down these neurons, resulting in less Orexin production (for contrast, Modafinil is an Orexin agonist). This has a manifold effect. First of all, less orexin=weight gain. Second, less orexin means less activation of the Locus Coeruleus, which is directly innervated by these Orexin neurons. So not only does it generally lower NE through alpha 2 agonism, it lowers it at its very source, as the Locus Coeruleus is the only place in the brain where NE is produced.

It finally all made fucking sense why the Clonidine was so effective, and after I found it, I was able to get off both the Zyprexa and Seroquel, plus other supplements I would use as sleep aids. I don't even take it any more, don't need it except on rare occurance. After I gained the weight and my circadian rhythm changed, my HPA axis seemed to reprogram itself so I no longer needed it. For the record though, when I was first on it, I was taking .6mg per night, a huge dose.

Long story short, Clonidine can regulate the HPA axis in times of sleep deprivation, by, in at least some part, working in the opposite way of Modafinil.

Edited by OneScrewLoose, 04 May 2015 - 09:39 PM.

[axonopathy]

I'm not recommending that anyone try this, but the morning after pill (mifepristone) is supposed to reset the HPA axis by antagonizing glucocorticoid receptors. Glucocorticoids are implicated in extreme chronic stress-induced neurotoxicity to hippocampal neurons. 

[ceridwen]

I don't think they'd give it to me being post menopausal

[OneScrewLoose]

I'm not recommending that anyone try this, but the morning after pill (mifepristone) is supposed to reset the HPA axis by antagonizing glucocorticoid receptors. Glucocorticoids are implicated in extreme chronic stress-induced neurotoxicity to hippocampal neurons.

Honestly looking for a study to support this.

[axonopathy]

 

I'm not recommending that anyone try this, but the morning after pill (mifepristone) is supposed to reset the HPA axis by antagonizing glucocorticoid receptors. Glucocorticoids are implicated in extreme chronic stress-induced neurotoxicity to hippocampal neurons.

Honestly looking for a study to support this.

 

 

Here you are: 

 

"The mechanisms underlying the pathophysiology of severe psychiatric illnesses are complex, involving multiple neuronal and neurochemical pathways. A growing body of evidence indicates that alterations in hypothalamic–pituitary–adrenal (HPA) axis function may be a trait marker in both mood disorders and psychosis, and may exert significant causal and exacerbating effects on symptoms and neurocognition. At present, however, no available treatments preferentially target HPA axis abnormalities, although many drugs do increase feedback-regulation of the HPA axis at the level of the glucocorticoid receptor (GR). This action may in part underpin their therapeutic efficacy. Therapeutic interventions directly targeted at GR function may therefore have clinical benefit. The present review examines the current literature for the clinical utility of GR antagonists (specifically mifepristone) in mood disorders and psychosis. At present, most studies are at the “proof-of-concept” stage, although the results of preliminary, randomized, controlled trials are encouraging. The optimum strategy for the clinical application of GR antagonists is yet to be established, their potential role as first-line or adjunctive treatments being unclear. The therapeutic utility of such drugs will become known within the next few years following the results of larger clinical trials currently underway."

 

Source: http://www.ncbi.nlm....les/PMC2671735/

 

"Animals respond to stress by activating a wide array of behavioral and physiological responses that are collectively referred to as the stress response. Corticotropin-releasing factor (CRF) plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, CRF initiates a cascade of events that culminate in the release of glucocorticoids from the adrenal cortex. As a result of the great number of physiological and behavioral effects exerted by glucocorticoids, several mechanisms have evolved to control HPA axis activation and integrate the stress response. Glucocorticoid feedback inhibition plays a prominent role in regulating the magnitude and duration of glucocorticoid release. In addition to glucocorticoid feedback, the HPA axis is regulated at the level of the hypothalamus by a diverse group of afferent projections from limbic, mid-brain, and brain stem nuclei. The stress response is also mediated in part by brain stem noradrenergic neurons, sympathetic andrenornedullary circuits, and parasympathetic systems. In summary, the aim of this review is to discuss the role of the HPA axis in the integration of adaptive responses to stress. We also identify and briefly describe the major neuronal and endocrine systems that contribute to the regulation of the HPA axis and the maintenance of homeostasis in the face of aversive stimuli."

 

Source: http://www.ncbi.nlm....les/PMC3181830/

 

Since mifepristone is a glucocorticoid antagonist, and since glucocorticoids are one of many mechanisms that regulate the HPA axis, it stands to reason that mifepristone would dampen the HPA stress response. This is the rational for mifepristone's potential use in the treatment of depression. (Source: http://www.ncbi.nlm....med/21694614). 

Edited by rnapolymerase, 04 May 2015 - 10:35 PM.

[FunkOdyssey]

 

I'm not recommending that anyone try this, but the morning after pill (mifepristone) is supposed to reset the HPA axis by antagonizing glucocorticoid receptors. Glucocorticoids are implicated in extreme chronic stress-induced neurotoxicity to hippocampal neurons.

Honestly looking for a study to support this.

 

 

There's are multiple threads about this already, here's one: http://www.longecity...is-dysfunction/

 

I don't want to discourage the discussion here, just suggesting a search to bring you up to speed first.

Edited by FunkOdyssey, 04 May 2015 - 11:27 PM.

[Flex]

I'm not recommending that anyone try this, but the morning after pill (mifepristone) is supposed to reset the HPA axis by antagonizing glucocorticoid receptors. Glucocorticoids are implicated in extreme chronic stress-induced neurotoxicity to hippocampal neurons. 

 

Serotonin is one of the main actors in Cortisol release.

So if Your HPA axis is deregulated, it might be due to Serotonin, besides the several mechanism where Cortisol reinforces him self via e.g. increased expression of FKBP 5 by cortisol

because FKBP5 decreases Glucocorticoid receptor expression and leads to a decreased negative feedback of Glucocrticoids; thus an increase :

 

Genetic association of FKBP5 and CRHR1 with cortisol response to acute psychosocial stress in healthy adults.

http://www.ncbi.nlm....pubmed/23274505

 

Heres a little overview of the implication of some Serotonin receptors:

(The 5-ht2C and its implication in anxiety and/or fear is obvious, so I dont mention it)

 

Effect of a series of 5-HT4 receptor agonists and antagonists on steroid secretion by the adrenal gland in vitro

http://www.researchg..._gland_in_vitro

 

Lysine is a partial 5-ht4 antagonist:

 

L-Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats.

http://www.ncbi.nlm....pubmed/14676321

 

The picture is indeed more complicated, even if You stay in the Serotonin system and look at e.g.  the 5-ht2b receptor:

Activation of 5-HT2B Receptors in the Medial Amygdala causes Anxiolysis in the Social Interaction Test in the Rat

http://www.sciencedi...028390897000427

 

5-HT2 ligands in the treatment of anxiety and depression

Because anxiety is a comorbid illness usually observed indepressed patients after acute administration of SSRIs,

the beneficial effects of 5-HT2A and 5-HT2C receptor antagonists or 5-HT2B receptor agonists on the antidepressant response could involve anxiolytic activities

http://www.neurophar...es/22917059.pdf

 

Leads to a release of Serotonine and Dopamine via activaton of the VTA and Raphe:

Role of Serotonin via 5-HT2B Receptors in the Reinforcing Effects of MDMA in Mice

http://journals.plos...al.pone.0007952

 

The problem here is that 5-ht2B activation leads to heart valve damages(or something like that) when taken over a longer period:

Drug-induced Valvulopathy: An Update

http://tpx.sagepub.c...t/38/6/837.full

 

AND

 

leads to an increase of arterial wall thickening which occurs in Users who take serotonine increasing  Antidepressants.

You might think that this thickening is good, but it actually decreases the elasticity of the vessels and leads therefore to hypertension and if I remember correctly (no guarantee!)

to an increase of hermorhages/bleeding

 

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

..recent studies confirmed that other 5-HT2B antagonists (terguride, PRX-08066, or C-122) significantly reduced pulmonary pressure, arterial wall thickening, and lumen occlusion but maintained cardiac function

http://www.bloodjour...so-checked=true

 

Btw: PPAR Y activation could decrease the expression of 5-ht2B and perhaps the thickening(?)

Peroxisome proliferator-activated receptor-γ ameliorates pulmonary arterial hypertension by inhibiting 5-hydroxytryptamine 2B receptor.

http://www.ncbi.nlm....pubmed/23108648

 

or the 5-ht7:

 

The 5-HT7 receptor: A key mechanism of endocrine dysregulation in stress-related disorders?

...Interestingly, pharmacological blockade of 5-HT7 receptors normalized
increased acute stress-induced corticosterone secretion in chronically stressed animals.

http://omicsonline.o....S1.005-030.pdf

Edited by Flex, 05 May 2015 - 04:02 PM.

[peakplasma]

Serotonin is one of the main actors in Cortisol release.

So if Your HPA axis is deregulated, it might be due to Serotonin

 

Could you please provide a bit of an explanation that might elucidate the relationship between serotonin and cortisol release? I didn't see it specifically addressed in the studies that you linked to.

I thought I read that direct serotonin-induced adrenocortical secretory response was entirely limited to ACTH and Corticosterone release. Of course, cortisol levels would rise in response to the feedback mechanism but that is mediated solely by an indirect downstream response to ACTH secretion; is there a parallel relationship between direct cortisol secretion and serotonin though? Or is it just via secondary mechanisms?

[OneScrewLoose]

@Flex. Fuck you, now I have a bunch of fascinating new research to do that will eat up even more of my time...thanks a lot... 

[Heisenburger]

@Flex. Fuck you, now I have a bunch of fascinating new research to do that will eat up even more of my time...thanks a lot... 

 

But, but...we live for this shit.

[OneScrewLoose]

I know...my precious time. 

[jack black]

Such a complicated part of our body/mind.

You know, at one point my insomnia was so bad, that I was on two anti psychotics (one being 10mg of Zyprexa) in order to just get to sleep. This only worked 50% of the time and made it nearly impossible for me to wake up in the morning. I then started taking clonidine for something else, and after 10+ prescriptions 15+ supplements, I finally found something that knocked me out 98% of the time, even if I tried to stay up. Sometimes I would be on the computer, on the couch, and just uncontrollably falling asleep. That NEVER happened to me before.

It also finally made me gain weight, after struggling and struggling to do so for 10 years. I would get as low as 130lbs at 5'11". I remember once losing 4 pounds in 4 days because of a lack of calories. And please, please don't fucking call this a golden problem, it's very different as a guy and no one treats you like a man at that wieght. Forget about being attractive to girls either. I was so self-conscious about it, that despite being 180lbs right now, I still have body dysmorphic disorder and see an image of myself at 145lbs, and can not even tell when I gain or lose weight until I step on a scale.

I could not, for the life of me, understand how Clonidine could possibly make me gain weight. I understood that it reduced norepinephrine levels and that's probably what put me to sleep, but I thought the weight thing was just coincidence or placebo. Then I found this study, which put it all together:

http://www.ncbi.nlm....les/PMC3035660/

You see, the orexin neurons in the lateral hypothalamus display alpha 2 receptors only in times of sleep deprivation, otherwise they are hidden. Activation of these receptors by Clonidine shuts down these neurons, resulting in less Orexin production (for contrast, Modafinil is an Orexin agonist). This has a manifold effect. First of all, less orexin=weight gain. Second, less orexin means less activation of the Locus Coeruleus, which is directly innervated by these Orexin neurons. So not only does it generally lower NE through alpha 2 agonism, it lowers it at its very source, as the Locus Coeruleus is the only place in the brain where NE is produced.

It finally all made fucking sense why the Clonidine was so effective, and after I found it, I was able to get off both the Zyprexa and Seroquel, plus other supplements I would use as sleep aids. I don't even take it any more, don't need it except on rare occurance. After I gained the weight and my circadian rhythm changed, my HPA axis seemed to reprogram itself so I no longer needed it. For the record though, when I was first on it, I was taking .6mg per night, a huge dose.

Long story short, Clonidine can regulate the HPA axis in times of sleep deprivation, by, in at least some part, working in the opposite way of Modafinil.

 

Super informative post. A few questions but first some info on my experience with clonidine.

I got some of it from an overseas pharmacy for ADHD treatment as Intuniv is not available as generic. I was too sedating for me for any daytime use even what taken in a small dose (50ug).

 

Then i learned about the REM suppressing action that helps with sleep apnea (that i unfortunately have). I tried it (regular dose of 100ug) for 2 nights in a row and that made me super tired during the next days.

 

Last night i was googling about REM sleep deprivation vs depression to find out the exact mechanisms (there are probably many) and found a study that suggested low dose clonidine (25ug) promoted REM sleep while a regular dose (150ug) reduced REM sleep (and apnea): https://www.ncbi.nlm...pubmed/15009817

 

So, i thought i used too small dose before and i took 200ug last night. I almost immediately fell asleep, and had a whole lots of vivid dreams in the morning before i woke up much much later than usually. I'm very sluggish, my head is heavy and fogged, and i'm trying to wake up with my usual strong coffee that is barely working this morning.

 

This reminds me my phosphatidylserine trial that produced tons of REM sleep with vivid dreams and made me tired and exhausted after a couple of nights of that.

 

So, my question is why the clonidine is not working for me? Am I taking too low dose for my 200+ weight, or is the dose too low by the end of night? Or is it that i have too little of that Orexin (i need to look it up) in the first place? I guess that would explain the issue with obesity. Maybe i should try that Modafinil to find out?

 

PS: turns out I've heard of orexin under its other name hypocretin, but didn't know much about it either.

 

 

Edited by jack black, 12 November 2016 - 04:59 PM.

[Kinesis]

Such a complicated part of our body/mind.

You know, at one point my insomnia was so bad, that I was on two anti psychotics (one being 10mg of Zyprexa) in order to just get to sleep. This only worked 50% of the time and made it nearly impossible for me to wake up in the morning. I then started taking clonidine for something else, and after 10+ prescriptions 15+ supplements, I finally found something that knocked me out 98% of the time, even if I tried to stay up. Sometimes I would be on the computer, on the couch, and just uncontrollably falling asleep. That NEVER happened to me before.

It also finally made me gain weight, after struggling and struggling to do so for 10 years. I would get as low as 130lbs at 5'11". I remember once losing 4 pounds in 4 days because of a lack of calories. And please, please don't fucking call this a golden problem, it's very different as a guy and no one treats you like a man at that wieght. Forget about being attractive to girls either. I was so self-conscious about it, that despite being 180lbs right now, I still have body dysmorphic disorder and see an image of myself at 145lbs, and can not even tell when I gain or lose weight until I step on a scale.

I could not, for the life of me, understand how Clonidine could possibly make me gain weight. I understood that it reduced norepinephrine levels and that's probably what put me to sleep, but I thought the weight thing was just coincidence or placebo. Then I found this study, which put it all together:

http://www.ncbi.nlm....les/PMC3035660/

You see, the orexin neurons in the lateral hypothalamus display alpha 2 receptors only in times of sleep deprivation, otherwise they are hidden. Activation of these receptors by Clonidine shuts down these neurons, resulting in less Orexin production (for contrast, Modafinil is an Orexin agonist). This has a manifold effect. First of all, less orexin=weight gain. Second, less orexin means less activation of the Locus Coeruleus, which is directly innervated by these Orexin neurons. So not only does it generally lower NE through alpha 2 agonism, it lowers it at its very source, as the Locus Coeruleus is the only place in the brain where NE is produced.

It finally all made fucking sense why the Clonidine was so effective, and after I found it, I was able to get off both the Zyprexa and Seroquel, plus other supplements I would use as sleep aids. I don't even take it any more, don't need it except on rare occurance. After I gained the weight and my circadian rhythm changed, my HPA axis seemed to reprogram itself so I no longer needed it. For the record though, when I was first on it, I was taking .6mg per night, a huge dose.

Long story short, Clonidine can regulate the HPA axis in times of sleep deprivation, by, in at least some part, working in the opposite way of Modafinil.

 

OSL, did you have any difficulty discontinuing clonidine?  I have a script for it, but have been reluctant to take much of it for fear of dependency.  I've also heard it can exacerbate depression, not something I need.  Nor do I need to gain weight, although weight isn't really a problem for me.  On the other hand, I've heard good things about it, not the least your experience.  And it does work for insomnia, which is an all-too-frequent issue for me.  Would be interested in any further thoughts you may have.