The Hunt For A Cyproheptadine Alternative Begins...

[Lokzo]

Hey guys,

Many of you will know my love/hate relationship with Cyproheptadine, in regards to PSSD/Anhedonia treatment.

I overheard on Danny Roddy's awesome podcast, that, Georgi Dinkov ( @haidut) is going to be releasing another broad spectrum serotonin antagonist.

Does anyone have any other updates in regards to the synthesis/development of this compound?

Sounds very exciting.

 

[dukesbobby777]

TBH he’s been on about releasing new stuff for the past year (or two), and nothing has arrived. So could be anyone’s guess. Nothing against him, because he’s an extremely busy guy.

 

[Jessie]

I'm not even sure a cypro alternative exists. You can replicate some of the effects with stuff like diphenhydramine and famotidine, diphenhydramine being an acceptable endotoxin antagonist, whereas famotidine can have anti-serotonin effects. But cypro does a lot more than just block TLR receptors and serotonin, it also lowers aldosterone, TSH, growth hormone, prolactin, endorphins. It essentially blocks the entire cascade of the stress cycle.

 

[Velve921]

Doxylamine succinate gives me more benefits 90% of the time.

 

[GAF]

While driving, I was listening to one of the Danny Roddy/Georgi podcasts and G said Ketotifen was close to cyproheptadine. Seems like it was in answer to a question near the end of the podcast. Sorry, not sure which podcast, but one of the more recent.

Ketotifen - Wikipedia

en.wikipedia.org

 

[miquelangeles]

Low dose doxepin (up to 10mg) will preferentially bind to H1 and 5HT2A. In high dose it is considered a "dirty drug" because it binds to a lot of receptors.
In low dose it is very safe and it feels very much like cyproheptadine without causing anhedonia. They are both tricyclics, structurally very similar.
For GI inflammation I would say doxepin is more effective than cyproheptadine, because it also binds to H2.

 

[Mito]

So, just a few quick comments. I have already tried 10-methoxyharmalan (10-MH) myself, and and off for a few months. The anti-serotonin effects are quite pronounced and can be felt at doses as low as 100mcg. This basically matches what the study on 10-MH serotonin antagonism found, as LSD is used clinically in doses of around 200mcg-400mcg daily but such doses are used to induce hallucinations. The anti-serotonin effects of LSD manifest even at doses as low as 50mcg, which is something studies with the closely related chemical lisuride also confirmed - i.e. while lisuride is used clinically in doses around 200mcg, doses in the 50mcg range still powerfully lower prolactin, while avoiding issues such as nausea and hypotension commonly seen with those chemicals. So, if 10-MH works similar to LSD but need 2-fold higher doses to produce the same effects, this means 100mcg should be able to match the effects of 50mcg lisuride but without the nausea, dizziness, etc. That is basically what I experienced when trying it.
The anti-serotonin effects (clear vision, stress-free digestion (even of starch), improved mood/cognition, relaxation, etc) of a single 200mcg dose of 10-MH usually last up to a day for me. Nausea does not seem to occur unless doses >1mg are reached but such high doses are quite unnecessary IMO as 100mcg-200mcg work quite well. I have tried up to 5mg as single doses and there are NO hallucinations, at least for me. Btw, despite LSD having a unique reputation as hallucinogen, virtually all ergot derivatives can cause hallucinations (and tremors) if used in high doses and/or for extended periods of time.
We have already started work on synthesizing it, so if the process is efficient and produces decent outputs, we should be able to release it in a month or so. We don't know yet if this would be commercially feasible. The papers listing its synthesis routes claim it should be relatively easy 1-2 step process but we have encountered several times in the past that published synthesis routes do not actually work as described. So, there is a good chance we will release this, but it is not guaranteed until we confirm the synthesis is possible and affordable (both in materials and manpower). In the meantime, you can get it from Sigma or other vendors selling it. I have not seen any indication that it is a controlled chemical in any country and all chemical vendors that sell it, do so without any restrictions or requiring any licenses.
From what is available in the scientific literature, 10-MH seems to be an anti-metabolite of both melatonin and serotonin and is present endogenously in the body. In other words, out bodies synthesized it from melatonin probably as part of a negative feedback mechanism to put the brakes on excessive serotonin/melatonin production/effects. Finally, 10-MH is structurally very similar to the 5-HT3 antagonist ondansetron, which IMO corroborates its effects as a serotonin antagonist, especially considering that the initial idea for developing ondansetron came precisely from work with the beta-carbolines / alkaloids like harmine, harmaline, and harmalan.

Ondansetron - Wikipedia

en.wikipedia.org

Also, the optimal doses of ondansetron for systemic health seem to be in the 0.5mg-1mg daily range (based on animal studies, and despite its clinical usage in 4mg doses) and this is what Ray has also been suggesting to people in regards to ondansetron dosing. So, the optimal dosing for 10-MH is probably in that same range (0,5mg-1mg daily), but in my experience even 100mcg daily produces noticeable anti-serotonin effects.


@Drareg @James b @Mauritio @MeatOrchid @Waynish @jmojo

 

[Mauritio]

I dont think this will ever come out .

@Lokzo
I have identified Ritanserin as a good cyproheptadine alternative. It has all the benefits of cypro ,but lacks the D2 antagonism .
But is couldn't find it anywhere .

 

[Mauritio]

Low dose doxepin (up to 10mg) will preferentially bind to H1 and 5HT2A. In high dose it is considered a "dirty drug" because it binds to a lot of receptors.
In low dose it is very safe and it feels very much like cyproheptadine without causing anhedonia. They are both tricyclics, structurally very similar.
For GI inflammation I would say doxepin is more effective than cyproheptadine, because it also binds to H2.

Have you taken it for some time ?
How does it feel ?
It seems to be an SSRI as well . And doesnt increase dopamine significantly. From its binding affinities I'd say it's pretty sedating...

"Doxepin is a reuptake inhibitor of serotonin and norepinephrine, or a serotonin–norepinephrine reuptake inhibitor (SNRI), and has additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities.[27][28] It is specifically an antagonist of the histamine H1 and H2 receptors, the serotonin 5-HT2A and 5-HT2C receptors, the α1-adrenergic receptor, and the muscarinic acetylcholine receptors (M1–M5)."

 

[ecstatichamster]

Doxylamine succinate gives me more benefits 90% of the time.

how do? @Velve921

 

[miquelangeles]

Have you taken it for some time ?
How does it feel ?
It seems to be an SSRI as well . And doesnt increase dopamine significantly. From its binding affinities I'd say it's pretty sedating...

"Doxepin is a reuptake inhibitor of serotonin and norepinephrine, or a serotonin–norepinephrine reuptake inhibitor (SNRI), and has additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities.[27][28] It is specifically an antagonist of the histamine H1 and H2 receptors, the serotonin 5-HT2A and 5-HT2C receptors, the α1-adrenergic receptor, and the muscarinic acetylcholine receptors (M1–M5)."

I’ve taken it for food allergies / intolerances. It feels very sedating first couple doses, but tolerance is built rather fast as with cyproheptadine. It is very effective for GI issues, IBS etc. Often prescribed to so called MCAS patients.
It is also marketed for insomnia under the name Silenor (6mg).
The antidepressant dose is 50mg and upwards.

 

[Velve921]

how do? @Velve921

For consistent, restful sleep, DS has a better effect (for me personally).

Cyproheptadine I use more so 1x a week when I’ve gone through many days of stress.

to give you a better picture, right now I’m going through a high stress period in my life due to a number of factors: losing my dad, being there for my mom, worldly situations, and being apart of a couple business ventures.

so on a week to week basis, I work Sunday-Friday then shut everything down on Saturday. However, sometimes stressful events pop up during the week that leaves me with challenging sleep. On a normal nightly basis, DS is perfect. However, when I have a rough patch, sleep is challenging regardless. Again, it’s because it’s a high stress time in my life.

when I have a rough patch, I’ll go a night or 2 with rough sleep then still have to perform during the day. So as you can imagine, serotonin starts building. When this happens, the Cyproheptadine at 2-4mg is extremely valuable to help me bounce back. If I did it on a nightly basis for general sleep, it doesn’t have that much of an effect at this point. But for my bounce backs, yes, it’s great that I have it.

last night I got home from work after a long week and I literally laid on my back like a snow angel, took cypro, then listened to some soothing sounds, and within 10 minutes I was out. When I woke this morning, it was a knew sense of calmness after the week.

For other people, I know cypro works wonders for sleep. I also think what I like about DS is that you can get it anywhere and it has really powerful effects.

hope this gives you a good frame.

 

[ecstatichamster]

For consistent, restful sleep, DS has a better effect (for me personally).

Cyproheptadine I use more so 1x a week when I’ve gone through many days of stress.

to give you a better picture, right now I’m going through a high stress period in my life due to a number of factors: losing my dad, being there for my mom, worldly situations, and being apart of a couple business ventures.

so on a week to week basis, I work Sunday-Friday then shut everything down on Saturday. However, sometimes stressful events pop up during the week that leaves me with challenging sleep. On a normal nightly basis, DS is perfect. However, when I have a rough patch, sleep is challenging regardless. Again, it’s because it’s a high stress time in my life.

when I have a rough patch, I’ll go a night or 2 with rough sleep then still have to perform during the day. So as you can imagine, serotonin starts building. When this happens, the Cyproheptadine at 2-4mg is extremely valuable to help me bounce back. If I did it on a nightly basis for general sleep, it doesn’t have that much of an effect at this point. But for my bounce backs, yes, it’s great that I have it.

last night I got home from work after a long week and I literally laid on my back like a snow angel, took cypro, then listened to some soothing sounds, and within 10 minutes I was out. When I woke this morning, it was a knew sense of calmness after the week.

For other people, I know cypro works wonders for sleep. I also think what I like about DS is that you can get it anywhere and it has really powerful effects.

hope this gives you a good frame.

yes it does. Thank you.

 

[BrianF]

Hey guys,

Many of you will know my love/hate relationship with Cyproheptadine, in regards to PSSD/Anhedonia treatment.

I overheard on Danny Roddy's awesome podcast, that, Georgi Dinkov ( @haidut) is going to be releasing another broad spectrum serotonin antagonist.

Does anyone have any other updates in regards to the synthesis/development of this compound?
used lo
Sounds very exciting.

I have used loratadine as a long term serotonin antagonist. I had none of the side effects you mention when using loratadine. But like you, i DID experience them on cypro. To the degree where i simply don't use it, despite having a supply in my bathroom cabinet.

 

[Lokzo]

I dont think this will ever come out .

@Lokzo
I have identified Ritanserin as a good cyproheptadine alternative. It has all the benefits of cypro ,but lacks the D2 antagonism .
But is couldn't find it anywhere .

Awesome man.

This drug also has the following property:

The 5-HT2 antagonist ritanserin blocks dopamine re-uptake in the rat frontal cortex​

 

[Mauritio]

Awesome man.

This drug also has the following property:

The 5-HT2 antagonist ritanserin blocks dopamine re-uptake in the rat frontal cortex​

Yes its actually pro dopaminergic. I've been looking for it one the web ,but couldnt find a vendor .

 

[CalmAmygdala]

Anyone know where to get ritanserin?

 

[Mauritio]

Anyone know where to get ritanserin?

Nope unfortunately not . The usual sites as sigma aldrich sell it but it's very expensive .

It was available via idelabs so maybe some of the OG members would like to sell it ?

 

[haidut]

Nope unfortunately not . The usual sites as sigma aldrich sell it but it's very expensive .

It was available via idelabs so maybe some of the OG members would like to sell it ?

Ritanserin contains fluorine, and not one but two of them. As such it has even higher potential for hepatotoxicity than chlorine containing antihistamine/antiserotonin chemicals. This is one of the main reasons we move away from it. It is also very difficult to synthesize, not only cost-wise but in terms of how many steps the total synthesis requires, and also the yield is very low.
Anyways, in regards to the potential for toxicity - even if you find a vendor, I would not use it for more than a few days and definitely not chronically.

 

[Mauritio]

Ritanserin contains fluorine, and not one but two of them. As such it has even higher potential for hepatotoxicity than chlorine containing antihistamine/antiserotonin chemicals. This is one of the main reasons we move away from it. It is also very difficult to synthesize, not only cost-wise but in terms of how many steps the total synthesis requires, and also the yield is very low.
Anyways, in regards to the potential for toxicity - even if you find a vendor, I would not use it for more than a few days and definitely not chronically.

Okay thanks for clarifying on the toxicity!
I wasn't aware how toxic it was ...