Cyphroheptadine Dosing. Establishing Optimal Dose To Antagonize Serotonin Without D3 Antagonism

[Kingpinguin]

Hi!

So according to many sources cyphroheptadine is a quite potent D3 antagonist.
D3 agonists show antidepressant effects and also strong increase in reward seeking behaviour, sexual desire and libido. I’ve personally noticed reduced desire, libido, motivation on higher doses of cyphroheptadine. But I’ve been looking for an good easy serotonin antagonist which mainly acts on the 5-ht2 receptors since most bad effects of serotonin are om these receptors. But with as little 5-ht1a antagonism and dopamine antagonism. 5-ht1a and 5-ht2c seems to be each others polar opposites where as one reduces dopamine, motivation sexual desire and the other reduces motivation, lowers dopamine, increases cortisol and prolactin. But finding a substance that seems safe/well researched does seem rather hard.
Metergoline seems to be one of the best options but it still antagonist at 5-ht1a.

anyway the antagonism of 5-ht1a of cyphroheptadine seems to be 59 nanomol (i assume this antagonism happens at 59 nanomol per liter? If anyone knows how to explain I’d appreciate that).

But all the 5-ht2 receptors only require 1-2 nM.

and D3 receptor 8 nM

So from the internet I found:
In 1L —-> 100 000ng/11000nmol =
9.09 nM

So my assumption a dose of 0,5mg fully absorbed cyphroheptadine would amount to 500 000ng in 1L. Humans contain about 4,7-5,5 liters of blood so lets say 5 liters then.
So now you can divide the 500 000ng back to 100 000ng again.
So this would mean with a cyphro dose of 0,5 you would hit 9,09 nM levels in your blood and that will be enough to have affinity for the dopamine D3 receptor as an antagonist which is at 8 nM.

Anyone who can answer if my thought pattern is correct?

Now I know absorption is not 100% and theres other variables to calculate for but you can at least halve the recommended dose of 0,5mg to get 0,25mg and a blood concentration of 4,5 nM which still would give a antagonistic effect of the bad 5-ht2 receptors with negliable effect on the dopamine system.

appreciate help with this calculation if anyone possess more knowledge than me how to calculate it precisly or if I’ve made any errors.

Need to find the oral dose of cyphroheptadine to obtain an nM level of 2,5-7 nM

@Cirion
I know you have a brain of a statistician. Think this calculation could be a interesting micro project for you

Peace
Homies.

 

[Kvothe]

So according to many sources cyphroheptadine is a quite potent D3 antagonist.

Can you provide a few?

 

[Kingpinguin]

Can you provide a few?

Cyproheptadine - Wikipedia

Values are Ki (nM). The smaller the value,
the more strongly the drug binds to the site.
The ↓ and ↑ indicate antagonist and
agonist type actions respectively.

Cyproheptadine[20]
Site Ki (nM) Action Species Ref
H1 0.06 ↓ Human
H2 ND ND
H3 >10,000 Human
H4 202 Human
M1 12 ↓ Human
M2 7 ↓ Human
M3 12 ↓ Human
M4 8 ↓ Human
M5 11.8 ↓ Human
5-HT1A 59 Human
5-HT2A 1.67 ↓ Human
5-HT2B 1.54 ↓ Human
5-HT2C 2.23 ↓ Human
5-HT3 228 Mouse
5-HT6 142 Human
5-HT7 123 Human
D1 117 Human
D2 112 ↓ Human
D3 8 Human
SERT 4,100 Rat
NET 290 Rat
DAT ND ND

Cyproheptadine is a very potent antihistamineor antagonist of the H1 receptor. At higher concentrations, it also has anticholinergic, antiserotonergic, and antidopaminergicactivities. Of the serotonin receptors, it is an especially potent antagonist of the 5-HT2receptors, and this underlies its effectiveness in the treatment of serotonin syndrome.


If you look at the table its receptor potency it says its a dopamine antagonist. It also specifically says in the text potent antihistamine and in higher doses it becomes an serotonin and dopamine antagonist. You might think it needs higher doses to block dopamine than serotonin but that is not true. The lower the value im the chart the more potent cyphro is at blocking the receptor. Histamine 1 receptor is 0,06 so its very potent. Most serotonin receptors are around 50-280. Only the 5ht-2 receptors cyphro is very potent antagonist with a value of 1,5-2,5. So it actually binds to dopamine D1, D2 more potently than what it binds to serotonin 3, 6, 7 receptors. And it binda to D3 receptors almost as potently as it binds to the 5ht-2 receptors. The chart basically says it becomes a dopamine antagonist around the same level it becomes an serotonin agonist.

this is in fact why you find Haidut and peat arguing for a very low dose such as 0,5mg. Because more than that will block dopamine aswell quite potently.

Now I personally am only interested in blocking the 5ht-2 receptors and not the other serotonin receptors. And luckily cyphro binds to those just before it starts binding to dopamine. So if you calibrate the dose you get antagonism at those serotomin receptors without blocking dopamine.
5ht-2 receptors are the worst serotonin receptors imo. Anyway according to my calculations you would need a cyphroheptadine dose of 0,1-0,35 mg to block histamine, serotonin 5ht-2 receptors and no dopamine blocking. At this level you would actually increase dopamine levels. Since blocking 5ht-2c helps increase dopamine and reduce prolactin. You just dont wanna get the dose high enough so cyphro itself starts blocking dopamine again.

if you want a potent serotonin antagonist without dopamine antagonism then metergoline is the best I could find so far

 

[Kvothe]

Cyproheptadine - Wikipedia

Values are Ki (nM). The smaller the value,
the more strongly the drug binds to the site.
The ↓ and ↑ indicate antagonist and
agonist type actions respectively.

Cyproheptadine[20]
Site Ki (nM) Action Species Ref
H1 0.06 ↓ Human
H2 ND ND
H3 >10,000 Human
H4 202 Human
M1 12 ↓ Human
M2 7 ↓ Human
M3 12 ↓ Human
M4 8 ↓ Human
M5 11.8 ↓ Human
5-HT1A 59 Human
5-HT2A 1.67 ↓ Human
5-HT2B 1.54 ↓ Human
5-HT2C 2.23 ↓ Human
5-HT3 228 Mouse
5-HT6 142 Human
5-HT7 123 Human
D1 117 Human
D2 112 ↓ Human
D3 8 Human
SERT 4,100 Rat
NET 290 Rat
DAT ND ND

Cyproheptadine is a very potent antihistamineor antagonist of the H1 receptor. At higher concentrations, it also has anticholinergic, antiserotonergic, and antidopaminergicactivities. Of the serotonin receptors, it is an especially potent antagonist of the 5-HT2receptors, and this underlies its effectiveness in the treatment of serotonin syndrome.


If you look at the table its receptor potency it says its a dopamine antagonist. It also specifically says in the text potent antihistamine and in higher doses it becomes an serotonin and dopamine antagonist. You might think it needs higher doses to block dopamine than serotonin but that is not true. The lower the value im the chart the more potent cyphro is at blocking the receptor. Histamine 1 receptor is 0,06 so its very potent. Most serotonin receptors are around 50-280. Only the 5ht-2 receptors cyphro is very potent antagonist with a value of 1,5-2,5. So it actually binds to dopamine D1, D2 more potently than what it binds to serotonin 3, 6, 7 receptors. And it binda to D3 receptors almost as potently as it binds to the 5ht-2 receptors. The chart basically says it becomes a dopamine antagonist around the same level it becomes an serotonin agonist.

this is in fact why you find Haidut and peat arguing for a very low dose such as 0,5mg. Because more than that will block dopamine aswell quite potently.

Now I personally am only interested in blocking the 5ht-2 receptors and not the other serotonin receptors. And luckily cyphro binds to those just before it starts binding to dopamine. So if you calibrate the dose you get antagonism at those serotomin receptors without blocking dopamine.
5ht-2 receptors are the worst serotonin receptors imo. Anyway according to my calculations you would need a cyphroheptadine dose of 0,1-0,35 mg to block histamine, serotonin 5ht-2 receptors and no dopamine blocking. At this level you would actually increase dopamine levels. Since blocking 5ht-2c helps increase dopamine and reduce prolactin. You just dont wanna get the dose high enough so cyphro itself starts blocking dopamine again.

if you want a potent serotonin antagonist without dopamine antagonism then metergoline is the best I could find so far

Thanks, but I am not convinced by this reference. The wikipedia reference leads you to the Ki Database, which leads you to this study (1), and judging by its' name this study will probably lead you to another one before you find the original reference. I can't access it because it's not available via sci-hub. If cyproheptadine was that strong a dopamine antagonist, why does it reliably lower prolactin in dozens of studies? I have taken 5-6mg for a long time and not noticed anything that feels like dopamine antagonism.
Regarding Peat and his recommendation: I have asked him, and he said that doses like 5-6mg are probably safe over a long time. He added that some people he knew needed doses of up to 24mg to feel right again.

(1) Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medi... - PubMed - NCBI

 

[milkboi]

Hi!

So according to many sources cyphroheptadine is a quite potent D3 antagonist.
D3 agonists show antidepressant effects and also strong increase in reward seeking behaviour, sexual desire and libido. I’ve personally noticed reduced desire, libido, motivation on higher doses of cyphroheptadine. But I’ve been looking for an good easy serotonin antagonist which mainly acts on the 5-ht2 receptors since most bad effects of serotonin are om these receptors. But with as little 5-ht1a antagonism and dopamine antagonism. 5-ht1a and 5-ht2c seems to be each others polar opposites where as one reduces dopamine, motivation sexual desire and the other reduces motivation, lowers dopamine, increases cortisol and prolactin. But finding a substance that seems safe/well researched does seem rather hard.
Metergoline seems to be one of the best options but it still antagonist at 5-ht1a.

anyway the antagonism of 5-ht1a of cyphroheptadine seems to be 59 nanomol (i assume this antagonism happens at 59 nanomol per liter? If anyone knows how to explain I’d appreciate that).

But all the 5-ht2 receptors only require 1-2 nM.

and D3 receptor 8 nM

So from the internet I found:
In 1L —-> 100 000ng/11000nmol =
9.09 nM

So my assumption a dose of 0,5mg fully absorbed cyphroheptadine would amount to 500 000ng in 1L. Humans contain about 4,7-5,5 liters of blood so lets say 5 liters then.
So now you can divide the 500 000ng back to 100 000ng again.
So this would mean with a cyphro dose of 0,5 you would hit 9,09 nM levels in your blood and that will be enough to have affinity for the dopamine D3 receptor as an antagonist which is at 8 nM.

Anyone who can answer if my thought pattern is correct?

Now I know absorption is not 100% and theres other variables to calculate for but you can at least halve the recommended dose of 0,5mg to get 0,25mg and a blood concentration of 4,5 nM which still would give a antagonistic effect of the bad 5-ht2 receptors with negliable effect on the dopamine system.

appreciate help with this calculation if anyone possess more knowledge than me how to calculate it precisly or if I’ve made any errors.

Need to find the oral dose of cyphroheptadine to obtain an nM level of 2,5-7 nM

@Cirion
I know you have a brain of a statistician. Think this calculation could be a interesting micro project for you

Peace
Homies.

This is what @haidut had to say about this on this thread Cyproheptadine's Effect On Dopamine:

You can take cypro together with lisuride. They really complement each other. Ask your doctor first of course.
Cypro has some dopamine antagonist properties on the D3 "receptor" and at really low concentrations too. So, taking even 1mg - 2mg would probably have some antagonistic effect on D3. This is where drugs like bromocriptine or lisuride can really help. The combination of 4mg cypro and 0.1mg lisuride can do wonder for mood, libido, energy, etc.
For more info look at the section Pharmacology on this page:
Cyproheptadine - Wikipedia

For the people who find cypro making them tired/depleted. It is probably due to the dose. If you look at the Wikipedia page, the concentration needed to antagonize the 5-HT1 and 5-HT2 "receptors" is about 2-3 nM/L. This is achievable with even 1mg cypro. The dopamine "receptors" D1, D2, and D3 are also antagonized by cypro. For D1 and D2, the concentration needed is about 100nM/L, which is achievable with 8mg single dose cypro.
Cyproheptadine - Wikipedia, the free encyclopedia
Given that long half life of cypro (9 hours) taking 4mg a few times a day can also probably achieve it over a few days. The D3 receptor is antagonized at concentrations of 8 nM/L, so taking lower dose cypro seems to have predominantly anti-serotonin effect withouht antagonizing dopamine except possibly D3. It is the dopamine antagonism at higher doses that probably makes some people feel like not doing anything.
Once again, Peat's knowledge is hard to deny given his recommendations of taking cypro at 1mg for general purposes and 2mg only for very serious conditions like cancer.

 

[Waynish]

I don't think it works that way. You'll have to titrate up. Start with one drop, or whatever your smallest dosage is... Increase until its medicinal effects are at peak. Skip dosages & decrease dosages when anything negative starts happening.

 

[milkboi]

I don't think it works that way. You'll have to titrate up. Start with one drop, or whatever your smallest dosage is... Increase until its medicinal effects are at peak. Skip dosages & decrease dosages when anything negative starts happening.

For me it kinda does work that way... anything over 0,5 mg Cypro lets me feel the anti-dopamine effect

 

[Kvothe]

For me it kinda does work that way... anything over 0,5 mg Cypro lets me feel the anti-dopamine effect

How exactely does the anti-dopamine effect feel? Have you tried higher doses than .5mg over a long time and did these effects still persist?

 

[Aries]

What do you think about mirtazapine? Ki values in wikipedia seem favorable for 5ht2 antagonism before affecting dopamine or 5ht1.

 

[milkboi]

How exactely does the anti-dopamine effect feel? Have you tried higher doses than .5mg over a long time and did these effects still persist?

Yes, I am taking Cypro for almost an year now. More days on than off I think. Feels like there was no tolerance build-up at all.

Supposed low dopamine Side effects are sluggishness, low motivation, depression etc. I think @Hans proposed that effects like that could also partly come from low histamine, so that might be a factor too.

 

[Kvothe]

Yes, I am taking Cypro for almost an year now. More days on than off I think. Feels like there was no tolerance build-up at all.

Supposed low dopamine Side effects are sluggishness, low motivation, depression etc. I think @Hans proposed that effects like that could also partly come from low histamine, so that might be a factor too.

I experienced extreme sluggishness and complete lack of motivation for about a week. I also slept for up to 15 hours for a few days, but all of this faded away. Ray also suggested that this is probably due to histamine antagonism.

@Kingpinguin Can you explain how exactely these dissociation constants are determined? I admit I haven't really made an effort to understand it in depth, but what I gathered from reading a few papers is that different tissues/organs sometimes show very different responses. For example, certain serotonin antagonists have very potent antagonist-effects in some parts of the brain, while they have no, or even an agonist effect, in other parts of the brain.

 

[DennisX]

Rauwolscine is a good 5Ht2b antagonist. Look it up on wiki. It can be bough on Amazon

 

[Kingpinguin]

Rauwolscine is a good 5Ht2b antagonist. Look it up on wiki. It can be bough on Amazon

nice find interesting

 

[Kingpinguin]

I experienced extreme sluggishness and complete lack of motivation for about a week. I also slept for up to 15 hours for a few days, but all of this faded away. Ray also suggested that this is probably due to histamine antagonism.

@Kingpinguin Can you explain how exactely these dissociation constants are determined? I admit I haven't really made an effort to understand it in depth, but what I gathered from reading a few papers is that different tissues/organs sometimes show very different responses. For example, certain serotonin antagonists have very potent antagonist-effects in some parts of the brain, while they have no, or even an agonist effect, in other parts of the brain.

Yes, I am taking Cypro for almost an year now. More days on than off I think. Feels like there was no tolerance build-up at all.

Supposed low dopamine Side effects are sluggishness, low motivation, depression etc. I think @Hans proposed that effects like that could also partly come from low histamine, so that might be a factor too.

Yes I have also experienced what I would call dopamine antagonism effects from cyphro specially at doses 1mg and up. But I still believe you get anti dopamine effect even between 0,5-1mg and that you could avoid it but still get the more positive serotonin antagonistic effects from a dose of 0,25 - 0,4 mg.
Yes the tired effects you can get from histamine. Modafinil which is known to cause insomnia has actually been shown to work as a primary histamine agonist in the brain so antagonism of histamine obviously can cause tiredness.

No im no expert at Ki values and understanding them but the lower the number the more affinity it has for the receptor. Or lower doses is needed to cause an effect. From what Haidut have previously said. Anything above 0,5mg of cyphro is enough to cause D3 antagonism. I just tried to calculate how he came to this assumption. He said it was based om the affinity number for the receptors.

obviously its effect in different tissues will vary depending if its a lipid soulable, water soulable or if it can cross the blood brain barrier. Different drugs accumulate differently. Dont think this has anything to do with the Ki

 

[Kvothe]

No im no expert at Ki values and understanding them but the lower the number the more affinity it has for the receptor. Or lower doses is needed to cause an effect. From what Haidut have previously said. Anything above 0,5mg of cyphro is enough to cause D3 antagonism. I just tried to calculate how he came to this assumption. He said it was based om the affinity number for the receptors.

The things is that haidut got the information from the same source as you, and as I said we can't even access the original publication. Most publications on cypro do not mention any anti-dopamine effects. Someone should experiment with a known, potent dopamine antagonist to see how it feels, and then compare it to larger doses of cypro. Any volunteers?

 

[milkboi]

The things is that haidut got the information from the same source as you, and as I said we can't even access the original publication. Most publications on cypro do not mention any anti-dopamine effects. Someone should experiment with a known, potent dopamine antagonist to see how it feels, and then compare it to larger doses of cypro. Any volunteers?

Sounds like a extremely fun experiment lol

 

[Kingpinguin]

The things is that haidut got the information from the same source as you, and as I said we can't even access the original publication. Most publications on cypro do not mention any anti-dopamine effects. Someone should experiment with a known, potent dopamine antagonist to see how it feels, and then compare it to larger doses of cypro. Any volunteers?

what original publication?

this is the source
PDSP Database - UNC

its from the psychoactive drug screening program.

This service provides screening of novel psychoactive compounds for pharmacological and functional activity at cloned human or rodent CNS receptors, channels, and transporters. Bryan Roth MD, PhD (University of North Carolina Chapel Hill) will perform pharmacological and functional screening of novel compounds as a contractor to NIMH. Screening of compounds is provided to qualified academic investigators at no cost.



This is basically where almost all pharmacology of druga are made and it clearly says cyphroheptadine is a dopamine antagonist.

on top of that I have been on a strong dopamine antagonist chlorpromazine because I had severe nausea and it also has antiemetic properties. Also used actual periactin a year now 4mg tablets and I’ve trialed up and down doses as high as 12mg at once and doses low as only 0,25mg. Imo cyphrohetadine is a clear antagonist of dopamine.
I also have restless leg syndrome which is scientifically proven to be caused by low dopamine. Almost all cyphroheptadine doses causes it to get worse. Only around 0,25 mg it seems not to have any effect on my rls.

if you do a bit of research you find out that basically all antihistamines that can cross the blood brain barrier has a dopamine lowering effect through lowering histamine.

Dopamine activity and histamine as a neurotransmitter is tightly connected in the brain.
An example is modafinil which if look at its mechanism of action is claimed to be through dopamine but the mechanism ”is not fully understood”. But deeper research shows that it acts as an histamine agonist but only in the brain. This leads to an upregulation of dopamine synthesis. And antihistamines leads to dopamine antagonism in the cns

 

[Kvothe]

what original publication?

this is the source
PDSP Database - UNC

I already explained this above. Their reference for the D3 number is this study: Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medi... - PubMed - NCBI
Judging by the title, this study will lead to another study, which might lead to another study. Claims like x is an agonist, or y is an antagonist of something are often "backed up" by these snowball claims that sometimes lead absolutely nowhere. It's like my uncle's best friend knows a guy who has heard from his mother that...

if you do a bit of research you find out that basically all antihistamines that can cross the blood brain barrier has a dopamine lowering effect through lowering histamine.

Can you show me some, I couldn't find anything.

 

[Kingpinguin]

I already explained this above. Their reference for the D3 number is this study: Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medi... - PubMed - NCBI
Judging by the title, this study will lead to another study, which might lead to another study. Claims like x is an agonist, or y is an antagonist of something are often "backed up" by these snowball claims that sometimes lead absolutely nowhere. It's like my uncle's best friend knows a guy who has heard from his mother that...



Can you show me some, I couldn't find anything.

No

https://www.researchgate.net/profil...ent-medications.pdf?origin=publication_detail

Here’s the paper.
Page 14 you find cyphroheptadine along with a bunch of other drugs they tested for. This is where the Ki values comes from.

 

[Kvothe]

Here’s the paper.
Page 14 you find cyphroheptadine along with a bunch of other drugs they tested for. This is where the Ki values comes from.

Great, thanks. I didn't see that it was a free download on researchgate.