How Cyproheptadine Lowers Stress

[haidut]

I posted several studies a few weeks ago showing that cyproheptadine completely prevents the rise of ACTH and cortisol during the night. All the studies were old or written in a foreign language so I did not have access to them and was not able to read how cyproheptadine was able to do its magic.
These studies claim that the stress-induced increases in cortisol are mediated through the 5-HT2C "receptor". Since cyproheptadine is a powerful antagonist at the 5-HT2C receptor this may explain a good portion of the effects cypro on blunting the stress response.
Perhaps even more importantly, drugs like cyproheptadine that antagonize 5-HT2C may prevent or even treat CVD and diabetes (type 2).

http://www.ncbi.nlm.nih.gov/pubmed/8637392/
"...That serotonin (5HT) is involved in regulating hypothalamic-pituitary- adrenal axis (HPA) function has long been recognized. A variety of drugs including precursors of 5HT such as 5HTP, drugs which release 5HT such as fenfluramine and drugs which act directly on 5HT receptors such as ipsapirone increase cortisol and ACTH concentrations. There is a general assumption that such stimulation occurs at a hypothalamic level. However, our increasing understanding of the complex interplay between 5HT and the HPA raises questions as to the validity of this simple model. An increasing volume of experimental research indicates that 5HT can act directly on the adrenal gland and possibly on the anterior pituitary as well. These findings have major implications for the interpretation of neuroendocrine studies of 5HT conducted in psychiatric conditions, such as depression."

http://www.ncbi.nlm.nih.gov/pubmed/17596444/
"...The dynamic interplay between serotonin [5-hydroxytryptamine (5-HT)] neurotransmission and the hypothalamic-pituitary-adrenal (HPA) axis has been extensively studied over the past 30 years, but the underlying mechanism of this interaction has not been defined. A possibility receiving little attention is that 5-HT regulates upstream corticotropin-releasing hormone (CRH) signaling systems via activation of serotonin 2C receptors (5-HT(2C)Rs) in the paraventricular nucleus of the hypothalamus (PVH). Through complementary approaches in wild-type rodents and 5-HT(2C)R-deficient mice, we determined that 5-HT(2C)Rs are necessary for 5-HT-induced HPA axis activation."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245751/

"...The serotonin 5HTR2C receptor has been shown to mediate HPA axis activation during stress. We hypothesized that a functional polymorphism (rs6318) of the 5HTR2C gene would be associated with HPA axis response to a laboratory stress protocol. The present sample consisted of 41 men (22 African Americans, 19 Caucasians). We found that at rest men with the more active rs6318 Ser23 C allele had similar cortisol values compared to those with the less active sys23 G allele. During laboratory stress, however, men with the Ser23 C allele exhibited the predicted significantly higher cortisol levels (p < .001), as well as larger increases in anger (P=0.08) and depressive mood (P=0.006) ratings, compared to the sys23 G carriers. The increase in cortisol was significantly related to the increases in ratings of anger and depression assessed before and after the emotion induction, and these correlations became nonsignificant when rs6318 genotype was covaried. We conclude that genetic variation in 5HTR2C may be associated with HPA axis activation and stimulated by emotional stress, and also with both psychological and physiological endophenotypes that increase the risk of cardiovascular disease and type 2 diabetes."

 

[jimmyquick]

Incredible Haidut!

Quick question for you. How does Diphenhydramine compare to Cyproheptadine? I use to take Diphenhydramine for sleep and it would make me progressively worse each day, such as in zero motivation and and overall feeling of just not caring about anything in life. I assumed this is an increase in seratonin as I read that Diphenhydramine can have mild SRI effects. This was dose of 25mg a day for about a month before I coulndt take it anymore. It was also causing me to retain a great deal of water.

However, dont some SRI or SSRI's eventually actually lower seratonin as the brain adjusts its output to compensate for the reuptake? Excused my ignorance, im just not well versed in the biochemistry of what is actually going on. Is Cyproheptatine acting in this same manner?

Im all about lowering ACTH and cortisol at night for sleep and wondering if I did so poorly on Diphenhydramine if Cyproheptadine would affect me in the same way. My prolactin still seems to be high and sometimes I still struggle with an appetite but I noticed Diphenhydramine seems to make it worse.

 

[miko]

Exercise downregulate 5-HT2c receptors:

"5-HT2C receptors in the basolateral amygdala and dorsal striatum are a novel target for the anxiolytic and antidepressant effects of exercise"

http://www.ncbi.nlm.nih.gov/pubmed/23049953

Mirtazapine also blocks 5-HT2c receptors (without blockade of SERT). The main problem with cyproheptadine, mirtazapine and other 5-HT2c antagonist is that they are very potent H1 antagonist - this knock out most of the people, causes sedation and sleepiness. But from the other side, antagonism of H1 is part of the cortisol lowering effects of this drugs.

 

[haidut]

Incredible Haidut!

Quick question for you. How does Diphenhydramine compare to Cyproheptadine? I use to take Diphenhydramine for sleep and it would make me progressively worse each day, such as in zero motivation and and overall feeling of just not caring about anything in life. I assumed this is an increase in seratonin as I read that Diphenhydramine can have mild SRI effects. This was dose of 25mg a day for about a month before I coulndt take it anymore. It was also causing me to retain a great deal of water.

However, dont some SRI or SSRI's eventually actually lower seratonin as the brain adjusts its output to compensate for the reuptake? Excused my ignorance, im just not well versed in the biochemistry of what is actually going on. Is Cyproheptatine acting in this same manner?

Im all about lowering ACTH and cortisol at night for sleep and wondering if I did so poorly on Diphenhydramine if Cyproheptadine would affect me in the same way. My prolactin still seems to be high and sometimes I still struggle with an appetite but I noticed Diphenhydramine seems to make it worse.

I personally don't like Bendaryl, it gave me weird feelings of dissociation even at 25mg. It also has SSRI activity in higher doses so I stay away from it, even though chemically it is similar to cypro.

 

[haidut]

Exercise downregulate 5-HT2c receptors:

"5-HT2C receptors in the basolateral amygdala and dorsal striatum are a novel target for the anxiolytic and antidepressant effects of exercise"

http://www.ncbi.nlm.nih.gov/pubmed/23049953

Mirtazapine also blocks 5-HT2c receptors (without blockade of SERT). The main problem with cyproheptadine, mirtazapine and other 5-HT2c antagonist is that they are very potent H1 antagonist - this knock out most of the people, causes sedation and sleepiness. But from the other side, antagonism of H1 is part of the cortisol lowering effects of this drugs.

Yes, all good points. In fact, I think all the -serins would be helpful - mianserin, ketanserin, ritanserin, flibanserin, etc.
As far as blocking H1 receptor - like you said, that's the point. I'd even throw in an H2 antagonist like famotidine since it will amplify the anti-stress effects. Sedation wears off after you have taken the H1 antagonists for several days.

 

[miko]

I have some HPA axis excessive activity (I would like to lower androstenedione, and other adrenal androgens) and I'm considering giving another try to mirtazapine (I have depression also) - it's the best drug for my depression (I think it's mainly because it's increasing dopamine in PFC via alpha-2 antagonism+5HT2c antagonism) but the problem is that overall sedation. I know that sedation wears to some point, but not not completely. SSRI drugs are crap (increasing HPA axis acitivity and other bad side effects like emotional blunting etc.) but they don't cause that sedation, sleepiness.

 

[firebreather]

@haidut is there something that lowers Adrenaline but not cortisol?

I've tried cypro many times in tablet and liquid form and after a night or two it actually seems to make my sleep worse. I've tried taking it at various times from 5pm to 10pm in varying doses.

My conclusion is that my cortisol is getting to low at night.

I say this because I've had my cortisol tested a few different times by blood serum, saliva and urine and every time it was either normal or low.

At my most stressed state it was barely out of single digits for the entire day.

It's almost as if for me when I'm really stressed adrenaline rises but cortisol lowers instead of both rising.

 

[haidut]

@haidut is there something that lowers Adrenaline but not cortisol?

I've tried cypro many times in tablet and liquid form and after a night or two it actually seems to make my sleep worse. I've tried taking it at various times from 5pm to 10pm in varying doses.

My conclusion is that my cortisol is getting to low at night.

I say this because I've had my cortisol tested a few different times by blood serum, saliva and urine and every time it was either normal or low.

At my most stressed state it was barely out of single digits for the entire day.

It's almost as if for me when I'm really stressed adrenaline rises but cortisol lowers instead of both rising.

Taurine, salt, adenosine, inosine, etc have all been shown to lower adrenaline or strongly oppose its effects.

 

[firebreather]

Taurine, salt, adenosine, inosine, etc have all been shown to lower adrenaline or strongly oppose its effects.

Thanks for the input @haidut . I use salt like it's going out of style.

I've tried up to 6mg of taurine in a day and the only real think I noticed from it was that it seemed to cause loose stools, but I will try a high dose at night. Inosine seemed like a a sugar pill (didn't do anything but that's very common for me with just about everything).

I'll look into where I can get Adenosine

Will Adenosine Triphosphate have the same effect or do I need to try and get the actual Adenosine?

 

[haidut]

Thanks for the input @haidut . I use salt like it's going out of style.

I've tried up to 6mg of taurine in a day and the only real think I noticed from it was that it seemed to cause loose stools, but I will try a high dose at night. Inosine seemed like a a sugar pill (didn't do anything but that's very common for me with just about everything).

I'll look into where I can get Adenosine

Will Adenosine Triphosphate have the same effect or do I need to try and get the actual Adenosine?

In the studies that I have seen ATP, hypoxanthine, xanthine, NAD, etc all lowered adrenaline secretion or increased its degradation. So, you can try ATP but it is probably going to be a lot more expensive than inosine. Btw, the inosine dose needed to see an effect is probably going to be at least 1g per pop, based on the studies I have seen.

 

[firebreather]

In the studies that I have seen ATP, hypoxanthine, xanthine, NAD, etc all lowered adrenaline secretion or increased its degradation. So, you can try ATP but it is probably going to be a lot more expensive than inosine. Btw, the inosine dose needed to see an effect is probably going to be at least 1g per pop, based on the studies I have seen.

I still have some inosine, I'll give 2g or more a try.

Do you know what the dose was for ATP that produced results?

 

[haidut]

I still have some inosine, I'll give 2g or more a try.

Do you know what the dose was for ATP that produced results?

I think ATP was more potent, but still needed 500mg to see big drop in adrenaline.

 

[firebreather]

I think ATP was more potent, but still needed 500mg to see big drop in adrenaline.

Well I can see how that could get expensive.

Tried 2g of Inosine 2 nights ago with no difference. I will try 2.5g tonight

 

[firebreather]

I think ATP was more potent, but still needed 500mg to see big drop in adrenaline.

I tried 500mg of ATP last might. Unfortunately i woke up just before 2am with a very stuffy nose and a need to urinate

 

[jb116]

I remember posting a response about ATP a while ago, somebody else was talking about it. ATP does have a different effect when ingested. In the intestine it'll degrade before reaching the mitochondria. Uric acid goes up consequently. May be histamine. The uric acid though could be protective, could also be problematic depending on the energy state. The inosine route as haidut mentioned might be better.

 

[mujuro]

Explains how it can treat bipolar or schizophrenia. The superior performance of atypical antipsychotics over the first generation dopamine destroyers in lowering stress markers and improving symptoms is attributed to their 5HT receptor activity. Something about that tricyclic skeleton. The old TCAs improve stress markers too. I remember an old paper on how TCAs work better in males vs females to "sensitize" central GRs to cortisol, thus improving bipolar symptoms.