Cyproheptadine - A Wonder Drug?

[Lokzo]

Anti-cholinergic drugs are good for the brain, even if they seem to impair short term memory. Choline, cocaine, and estrogen "improve" memory through the same mechanism - i.e. excitotoxicity. Anything that excites the brain cells will probably improve memory in the short run but in the long run will kill brain cells and cause some type of neurodegenerative condition. Just look at all the trials for Alzheimers using cholinergic drugs - i.e. they all failed.
viewtopic.php?f=10&t=4229

Choline does not cause Excitoxicity @haidut
CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons. - PubMed - NCBI

 

[Beefcake]

Choline does not cause Excitoxicity @haidut
CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons. - PubMed - NCBI

Like to add
Choline release and inhibition of phosphatidylcholine synthesis precede excitotoxic neuronal death but not neurotoxicity induced by serum deprivation - PubMed - NCBI
These results show that the increase in extracellular choline induced by NMDA receptor activation is directly related with excitotoxic cell death and indicate that choline release is an early event of the excitotoxic process produced by inhibition of phosphatidylcholine synthesis and not by activation of membrane phospholipid degradation.

So i guess this means the glutamate force the cells to release choline thus lowering phosphatidylcholine synthesis. Phosphatidylcholine is neuroprotective since its part of the membrane structure
Neuroprotective Actions of Dietary Choline

 

[Lokzo]

Like to add
Choline release and inhibition of phosphatidylcholine synthesis precede excitotoxic neuronal death but not neurotoxicity induced by serum deprivation - PubMed - NCBI
These results show that the increase in extracellular choline induced by NMDA receptor activation is directly related with excitotoxic cell death and indicate that choline release is an early event of the excitotoxic process produced by inhibition of phosphatidylcholine synthesis and not by activation of membrane phospholipid degradation.

So i guess this means the glutamate force the cells to release choline thus lowering phosphatidylcholine synthesis. Phosphatidylcholine is neuroprotective since its part of the membrane structure
Neuroprotective Actions of Dietary Choline

Great contributions, thanks.

 

[haidut]

Choline does not cause Excitoxicity @haidut
CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons. - PubMed - NCBI

Depends on the dose, and in the doses people gobble up as supplements it is definitely toxic.

Why are neurotransmitters neurotoxic? An evolutionary perspective
"...As far as we are aware, there is currently no experimental evidence of direct ACh toxicity. However, the overstimulation of ACh receptors as a result of ACh accumulation that is caused by acetylcholinesterase inhibition can lead to cholinergic toxicity 47, 48. This toxicity may involve the release of choline from phosphatidylcholine that is downstream of muscarinic ACh receptors 49, leading to phosphatidylcholine depletion. In addition, the use of nicotinic ACh receptor antagonists has shown to reduce the neurotoxicity of the Alzheimer’s disease-related peptide, β-amyloid 50. ACh interacts with lipid bilayers and elicits changes in the organization of the lipid bilayer 51. This interaction is non-specific, slower than receptor activation, and has a longer duration 46. We speculate that the accumulation of ACh could interfere with the membrane morphology 46 and consequently may interfere with its function."

 

[Lokzo]

Depends on the dose, and in the doses people gobble up as supplements it is definitely toxic.

Why are neurotransmitters neurotoxic? An evolutionary perspective
"...As far as we are aware, there is currently no experimental evidence of direct ACh toxicity. However, the overstimulation of ACh receptors as a result of ACh accumulation that is caused by acetylcholinesterase inhibition can lead to cholinergic toxicity 47, 48. This toxicity may involve the release of choline from phosphatidylcholine that is downstream of muscarinic ACh receptors 49, leading to phosphatidylcholine depletion. In addition, the use of nicotinic ACh receptor antagonists has shown to reduce the neurotoxicity of the Alzheimer’s disease-related peptide, β-amyloid 50. ACh interacts with lipid bilayers and elicits changes in the organization of the lipid bilayer 51. This interaction is non-specific, slower than receptor activation, and has a longer duration 46. We speculate that the accumulation of ACh could interfere with the membrane morphology 46 and consequently may interfere with its function."

Very interesting. I'll look into this...

 

[Beefcake]

Depends on the dose, and in the doses people gobble up as supplements it is definitely toxic.

Why are neurotransmitters neurotoxic? An evolutionary perspective
"...As far as we are aware, there is currently no experimental evidence of direct ACh toxicity. However, the overstimulation of ACh receptors as a result of ACh accumulation that is caused by acetylcholinesterase inhibition can lead to cholinergic toxicity 47, 48. This toxicity may involve the release of choline from phosphatidylcholine that is downstream of muscarinic ACh receptors 49, leading to phosphatidylcholine depletion. In addition, the use of nicotinic ACh receptor antagonists has shown to reduce the neurotoxicity of the Alzheimer’s disease-related peptide, β-amyloid 50. ACh interacts with lipid bilayers and elicits changes in the organization of the lipid bilayer 51. This interaction is non-specific, slower than receptor activation, and has a longer duration 46. We speculate that the accumulation of ACh could interfere with the membrane morphology 46 and consequently may interfere with its function."

So does ACh agonist like nicotine worsen ahlzeimers?

 

[haidut]

So does ACh agonist like nicotine worsen ahlzeimers?

Possibly yes, but it seems to protect against Parkinson due to its indirect dopaminergic and antiestrogenic effects.
Nicotine tied to Alzheimer's risk
Dietary nicotine and Parkinson's disease: Evidence and relationship

 

[Lokzo]

Cyproheptadine works the best before bed, only when administered 3-4 hours before.

If I take it DIRECTLY before bed, it worsen's my DEEP sleep scores.

Timing is critical.

 

[Sativa]

Choline does not cause Excitoxicity

looking at the entire organism/brain in an interconnected manner, then ofc excess ACh is bound to be undesirable, probably undermining general coherence... especially considering the Acetylcholine system is directly linked to the Dopamine system.

Dopaminergic and cholinergic interaction in cataleptic responses in mice. - PubMed - NCBI
Note that in the article they state the Dopamine and Muscarinic receptors act in a synergistic fashion when it comes to dopamine, but separate when it comes to other systems (such as cholinergic systems)​

Cyproheptadine works the best before bed

Has anyone ever tried mimicking Cypro's pharmacology using other substances/mechanisms? shouldn't be too complicated, Cypro's moa's seem simple enough.

Cyproheptadine has anti-psychotic & anti-schizophrenia properties (histamine is implicated, perhaps via its link to Orexin & cannabinoid systems)

Worth noting - long-term use of 'receptor' antagonists, will generally result in up-regulation of said 'receptor system', which in the case of serotonin receptors, might be questionable / undesirable under some circumstances...
Generally, 'antagonising' aka blocking receptors, has the effect of increasing their number/density, aka, the receptors get up-regulated.
A Serotonin antagonist will, in the mid to long-term, result in increased serotonin receptors. Since serotonin HT1A activation reduces / dampens all other serotonin receptors, maybe there is some respite...

These results suggest that an upregulation of muscarinic ACh receptors is produced by repeated clomipramine administration - a muscarinic antagonist ...and such a change is responsible for the decreased sensitivity to the muscarinic antagonist scopolamine.​

 

[Sativa]

Haidut:

Ray Peat has mentioned cyproheptadine as a possible option for correcting certain physiological processes that have been derailed after years of eating PUFA, being exposed to chronic stress, toxins, endotoxin, battling chronic diseases, etc.
...
whenever a substance displays a wide variety of protective/curative effects via multiple "pathways", it suggests that the theory behind it is probably correct.​

To mimic Cypro's pharmacology, you would simply recreate the up-stream & down-stream effects of Cypro's various properties.
Assuming - that is, that no natural solutions for the varied antagonism already exist; such as is the case for the age-old time-tested botanical anti-cholinergic's.

That leaves 2 other big influences, serotonin & histamine (and other's no doubt)

There are enough fairly clean acting OTC anti-serotonin solutions mentioned by RP/on this forum.
As for histamine, it's surrounding dynamics are fairly well researched.
GABA activators seem to dampen excessive histamine activity.
Cannabinoids seem to increase histamine activity. Endocannabinoids play a potent role in Peat world, especially since mitochondria have CB1 'receptors'...
NOTE: All PUFA's - endogenous & exogenous - are metabolized into endo-cannabinoids...!
You literally can't escape them.

A CB1 agonist increased histamine release from the posterior hypothalamus, where the histaminergic tuberomamillary nuclei (TMN) are located...
-
The modulatory effect of cannabinoids on histamine release apparently did not involve GABA inhibition, which provides the main inhibitory input to the histaminergic neurons in the hypothalamus
source: Differential effect of cannabinoid agonists and endocannabinoids on histamine release from distinct regions of the rat brain. - PubMed - NCBI
​

There's a dopamine link too.
Anti-histamine's can increase dopamine.
Histamine can potentially stimulate prolactin (which lowers dopamine)

...histamine also acts to control and regulate the production and release of other neurotransmitters, including dopamine.
For example, medications which block histamine can increase dopamine release, while histamine also stimulates prolaction releases, known to inhibit dopamine, and the activation of histamine production in certain cells causes a decrease in dopamine production by these cells.​

Another aspect to things... histamine influencing serotonin:

- It can be concluded that histamine stimulates serotonin, norepinephrine, and dopamine transmission in certain areas of the brain.
- Release of acetylcholine, norepinephrine & serotonin are all controlled in part by histamine levels
- Histamine stimulates prolactin release via H2 receptor, which in turn inhibits dopamine production.
​

Anyway... this just allows you to pick & choose which aspects of Cypro are most suitable and compatible for you, thus minimizing any of Cypro's potentially undesirable aspects, whilst maximizing it's subjective beneficial aspects.

Obv, you can do this with anything - I copy certain aspects of Progesterone for example.
Whatever it is, take it apart, then use the bits you find most desirable...

Aside insight on Mast Cells & Histamine:

Mast cells contain dopamine, a hormone and neurotransmitter. This chemical is most often associated with reward seeking behavior, including addiction behaviors. It also has other important roles, including motor functions. Mast cell activation causes depletion of dopamine as frequent degranulation causes a decrease in dopamine production by these cells. Dopamine can be converted to norepinephrine. In blood vessels, dopamine inhibits norepinephrine release and acts as vasodilator. Dopamine also increases sodium excretion and urine output, reduces insulin production, reduces GI motility, protects intestinal mucosa and reduces activity of lymphocytes. It is responsible for cognitive alertness.
source: Research Notes on Allergies, Histamine and Parkinson’s Disease | Facebook​

 

[Sativa]

re serotonin HT2A - activation increases serotonin, like SSRI's!

HT2A activation increase the amount of an enzyme Protein Kinase C.
One of PKC's functions is as a Serotonin Reuptake Inhibitor, but it does this by phosphorylating the cell receptor instead of blocking it. This increases the amount of serotonin in the synapse and the length of time the serotonin stays in the synapse.​

HT2A also stimulates significant endocannabinoid production... = potential histamine activation

HT1A has the opposite effect of HT1A; reducing serotonin aka an inhibitory effect on the amount of serotonin in the synapse.

an aside... HT1A also stimulates Oxytocin release, a bonding/trust/'naiveness' hormone, naturally released for scenarios such as mother-baby bonding etc.

5-HT2 stimulates ACTH, Corticosterone, Oxytocin, Renin, and Prolactin Release and Activate Hypothalamic CRF and Oxytocin-Expressing Cells
5-HT2A Receptors Stimulate ACTH, Corticosterone, Oxytocin, Renin, and Prolactin Release and Activate Hypothalamic CRF and Oxytocin-Expressing Cells​

 

[Sativa]

@aguilaroja @BigYellowLemon @managing @Rafael Lao Wai

 

[Sativa]

To mimic Cypro's pharmacology, you would simply recreate the up-stream & down-stream effects of Cypro's various properties.
Assuming - that is, that no natural solutions for the varied antagonism already exist; such as is the case for the age-old time-tested botanical anti-cholinergic's.

Ray wrote in some of his articles that estrogen mediates its effects through histamine and the cholinergic system, so anti-histamines and anti-cholinergic drugs can block estrogen's effects.

Ray has written about the excititoxic properties of acetylcholine, and how estrogen manifests its effects through the cholinergic system.

Probably why all the traditional anti-cholinergic botanicals are so popular...
The cholinergic system is directly linked to the dopamine system, research indicates via M1/M2 & D1/D2 interactions, and that's just what's 'known'.
Even Ray Peat himself seems certain lol

...as well as chemicals that mimic the effects of acetylcholine, such as the organophosphate insecticides, can impair the ability to think and learn.

 

[Sativa]

Excessive oxytocin release, from serotonin-'overload', is likely a significant factor involved in the effects of SSRI drugs...oxtyocin makes you feel good, yet psychologically vulnerable... a prime target, psychologically speaking, for any predatory elements...
anyway...
Limonene from citrus essential oils is a pleasant sustainable Oxytocin one though, nice and psychoactive...

HT1A also stimulates Oxytocin release, a bonding/trust/'naiveness' hormone

by H Jørgensen - ‎2003

Vasopressin & oxytocin secretion was stimulated by 5-HT, the 5-HT(1A+1B+5A+7) agonist 5-carboxamidotryptamine (5-CT), the 5-HT(2A+2C) agonist DOI, the 5-HT(2C+2A) agonist mCPP, the 5-HT(2C) agonist MK-212, the 5-HT(3) agonist SR 57277 and the 5-HT(4) agonist RS 67506.
The 5-HT(1A) agonist 8-OH-DPAT, which had no effect on vasopressin secretion, stimulated oxytocin secretion.
The 5-HT-induced release of vasopressin and oxytocin was inhibited by central infusion of the 5-HT antagonists ​

 

[Lokzo]

Incredible insights and analysis @Sativa

Why would something like Nelumbo Nucifera make me feel ACUTELY incredibly good, like all feelings and emotions come back, but then later on leave me back in the NUMBED state.

Nelumbinis Semen reverses a decrease in 5-HT1A receptor binding induced by chronic mild stress, a depression-like symptom. - PubMed - NCBI


I am still not sure what the Cypro does to the 5-HT1A receptor on the rebound, because that drug acutely makes me feel horrible but then 3-4 days later has this amazing rebound effect.

 

[Lokzo]

re serotonin HT2A - activation increases serotonin, like SSRI's!

HT2A activation increase the amount of an enzyme Protein Kinase C.
One of PKC's functions is as a Serotonin Reuptake Inhibitor, but it does this by phosphorylating the cell receptor instead of blocking it. This increases the amount of serotonin in the synapse and the length of time the serotonin stays in the synapse.​

HT2A also stimulates significant endocannabinoid production... = potential histamine activation

HT1A has the opposite effect of HT1A; reducing serotonin aka an inhibitory effect on the amount of serotonin in the synapse.

an aside... HT1A also stimulates Oxytocin release, a bonding/trust/'naiveness' hormone, naturally released for scenarios such as mother-baby bonding etc.

5-HT2 stimulates ACTH, Corticosterone, Oxytocin, Renin, and Prolactin Release and Activate Hypothalamic CRF and Oxytocin-Expressing Cells
5-HT2A Receptors Stimulate ACTH, Corticosterone, Oxytocin, Renin, and Prolactin Release and Activate Hypothalamic CRF and Oxytocin-Expressing Cells​

Maybe I need the 5-HT2A activation, because I have low cortisol and ACTH?!?!

 

[Adrenaline]

Maybe I need the 5-HT2A activation, because I have low cortisol and ACTH?!?!

As you can see it will also increase other stress promoters like prolactin, renin, oxytocin.

I think you need a short-term glucocorticoid. It will just upregulate ACTH and cortisol. Much safer then activating whole serotonin response.

 

[Lokzo]

short-term glucocorticoid. It will just upregulate ACTH and cortisol

I considered this route.

Any particular one you think would be worth experimenting with?

 

[Adrenaline]

I considered this route.

Any particular one you think would be worth experimenting with?

Prednisone or dexamethasone are generally preffered.

 

[Eric88]

Thank you OP, from your username I assume in Europe you live nearby to me. I can't find any Cypro in Bulgarian pharmacies. I took (only) Mirtazapine but experienced same Serotonin syndrome as I did on SJW or SSRIs. Turns out it can cause serotonin syndrome: https://www.google.com/search?ie=UT...roid-browser&q=Mirtazapine+serotonin+syndrome

Could Cypro cause SS as well or not? I know they use it against serotonin toxicity/syndrome so maybe it doesn't work exactly like Mirtazapine? Also how can I buy Cypro in the EU legally? I'm hyperthyroid, hyper T and hyper afternoon cortisol guy that's also depressed/anhedonic. Apparently I'm high serotonin and I want to detox from years of antidepressant/5htp/SJW.